Aryl substituted pyrido[1,4]benzodiazepines and their use as antidepressives

ABSTRACT

Novel [2-[(aminopyridinyl)amino]phenyl]arylmethanones and their thioxomethyl, ketal or thioketal analogs of the formula: ##STR1## wherein; R is selected from the group consisting of hydrogen, loweralkyl, --alk 1  --halo, --alk 1  --NR 1  --NR 1  R 2  or --alk 1  --N═CH--OC 2  H 5  ; 
     R 1  and R 2  are selected from the group consisting of hydrogen, loweralkyl, --C(O)O-loweralkyl or R 1  and R 2  taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and 4-substituted-1-piperazinyl; 
     B is selected from carbonyl, thioxomethyl, ketal or thioketal; 
     Ar is selected from the group consisting of 2, 3 and 4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected from halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be the same of different; 
     alk 1  is a straight or branched hydrocarbon chain containing 1-8 carbon atoms; 
     Z is selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy or nitro; 
     Y is selected from the group consisting of hydrogen or 1-2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same of different, 
     and the acid addition salts thereof. 
     These compounds are intermediates in the preparation of novel aryl substituted pyrido[1,4]benzodiazepines having antidepression activity. Some of these intermediates are useful in treating depression.

This is a division of application Ser. No. 395,218, filed July 6, 1982,now U.S. Pat. No. 4,447,361, and a continuation-in-part application ofcopending application Ser. No. 305,080 filed Sept. 24, 1981 nowabandoned.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to certain novelpyrido[1,4]benzodiazepines and novel chemical intermediates andpharmaceutical methods and compositions for treating depression inhumans.

2. Description of the Prior Art

Wander, A., in British Pat. No. 907,646 discloses preparation of certaindibenzodiazepines substituted with phenyl radicals on carbon and withalkyl or aminoalkyl radicals on the bridging nitrogen atom between thephenyl rings.

Greig, M. E., et al., J. Med. Chem. 14 No. 2, page 153 (1971), disclosedibenzodiazepines similar to the foregoing Wander disclosure usefulagainst anaphylactic shock.

Japanese Patent 73/43,520 (C.A. 80: 133501n discloses6-phenyl-2,3,4,4a-tetrahydro-11H-pyrido[2,3-b][1,4]benzodiazepineshaving anticonvulsant activity which are illustratively prepared from2-aminobenzophenones and ornithine.

SUMMARY OF THE INVENTION

The novel pyrido[1,4]benzodiazepines of the present invention have theformula ##STR2## wherein;

R is selected from the group consisting of hydrogen, loweralkyl, --alk¹--halo, --alk¹ --NR¹ R² or --alk¹ --N═CH--OC₂ H₅ ;

R¹ and R² are selected from the group consisting of hydrogen,loweralkyl, --C(O)O-loweralkyl, or R¹ and R² taken together with theadjacent nitrogen atom may form a heterocyclic residue selected from thegroup consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl,4-morpholinyl, 1-piperazinyl, and 4-substituted-1-piperazinyl;

Ar is selected from the group consisting of 2, 3 and 4-pyridinyl, 2 or3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected fromhalo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be thesame or different;

Alk¹ is a straight or branched hydrocarbon chain containing 1-8 carbonatoms;

Z is selected from the group consisting of hydrogen, halogen,loweralkyl, loweralkoxy, hydroxy or nitro;

Y is selected from the group consisting of hydrogen or 1-2 radicalsselected from loweralkyl, loweralkoxy or hydroxy and may be the same ordifferent;

n is 0 and 1 and when n is zero the dotted line is a double bond, andthe acid addition salts thereof.

The compounds of Formula I have utility as antidepressants for treatingdepression or as intermediates in the preparation of other compounds ofFormula I.

The novel [2-[(aminopyridinyl)amino]phenyl]arylmethanones and theirthioxomethyl, ketal or thioketal analogs which form in the reactionmixture prior to cyclization to diazepines and certain of which haveadditional utility as antidepressants for treating depression arerepresented by the formula: ##STR3## wherein B is selected fromcarbonyl, thioxomethyl, ketal or thioketal, and R, R¹, R², Ar, alk¹, Zand Y are as defined under Formula I above.

In the further definition of symbols in the formulas hereof and wherethey appear elsewhere throughout this specification and claims, theterms have the following significance.

The "alk" straight or branched connecting hydrocarbon chain containing1-8 carbons is exemplified by methylene (--CH₂ --), ethylene (--CH₂--CH₂ --), propylene (--CH₂ CH₂ CH₂ --), ethylidene ##STR4##1,2-propylene ##STR5## isopropylidine ##STR6## or 1,3-butylene ##STR7##and the like.

The term "loweralkyl" includes straight and branched chain hydrocarbonradicals of up to eight carbon atoms inclusive and is exemplified bysuch groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.

The term "halogen" includes chlorine, bromine, fluorine, and iodine,preferably chlorine, bromine and fluorine.

The term "4-substituted-1-piperazinyl" refers to piperazine substitutedin the 4-position by loweralkyl or alkoxy-carbonyl blocking group whichmay subsequently be removed to give the unsubstituted piperazine.

Pharmaceutically acceptable acid addition salts are those salts formedby the pyridobenzodiazepines and the[2-[(aminopyridinyl)amino]phenyl]arylmethanones of Formula IIphereinbelow of this invention with any acid which is physiologicallycompatible in warm blooded animals, such salts being formed either bystrong or weak acids. Representative of strong acids are hydrochloric,sulfuric and phosphoric acids. Representative of weak acids are fumaric,maleic, succinic, oxalic, cyclohexamic and the like.

The 6-aryl-11H-pyrido[2,3-b][1,4]benzodiazepines and the 5,6-dihydroderivatives thereof encompassed by Formula I have the formula ##STR8##

The 6-aryl-11H-pyrido[3,4-b][1,4]benzodiazepines and the 5,6-dihydroderivatives thereof encompassed by Formula I have the formula ##STR9##

The 10-aryl-5H-pyrido[4,3-b][1,4]benzodiazepines and the 10,11 dihydroderivatives thereof encompassed by Formula I have the formula ##STR10##

The 10-aryl-5H-pyrido[3,2-b][1,4]benzodiazepines and the 10,11 dihydroderivatives thereof encompassed by Formula I have the formula ##STR11##

In all the formulas Iw to Iz, the symbols R, Ar, Z and Y have thedefinition given hereinabove under Formula I.

For the purpose of testing antidepressant activity of the presentinvention compounds, the procedure given by Englehardt, E. L., et al.,J. Med. Chem. 11(2): 325 (1968) which has been indicative in the past ofusefulness of compounds for treating human depression was used asfollows: 20 mg/kg of the compound to be tested was administered to fiveadult female mice (ICR-DUB strain), intraperitoneally 30 minutes priorto the administration of a ptotic dose (32 mg/kg IP) of tetrabenazine(as the methane sulfonate salt). Thirty minutes later, the presence orabsence of complete eyelid closure (ptosis) was assessed in each animal.An ED₅₀ (Median Effective Dose) may be established for each testedcompound in blocking tetrabenazine induced ptosis in mice following theprocedure given by Litchfield et al., J Pharmacol. Exp. Therap. 96:99-113 (1949).

Compounds of the invention encompassed by Formula I which haveantidepressant activity in the foregoing procedure have the Formula Ip##STR12## wherein;

R is selected from the group consisting of hydrogen, loweralkyl or--alk¹ --N--R¹ R² ;

R¹ and R² are selected from the group consisting of hydrogen, loweralkylor R¹ and R² taken together with the adjacent nitrogen atom may form aheterocyclic residue selected from the group consisting of1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl or4-loweralkyl-1-piperazinyl;

Ar is selected from the group consisting of 2, 3 or 4-pyridinyl, 2 or3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected fromhalo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be thesame or different;

Alk¹ is a straight or branched hydrocarbon chain containing 1-8 carbonatoms;

Z is selected from the group consisting of hydrogen, halogen,loweralkyl, loweralkoxy, hydroxy or nitro;

Y is selected from the group consisting of hydrogen, or 1-2 radicalsselected from loweralkyl, loweralkoxy or hydroxy and may be the same ordifferent;

n is 0 and 1 and when n is zero the dotted line is a double bond, andthe pharmaceutically acceptable acid addition salts thereof.

The compounds of Formula Ip wherein R is --alk¹ --NR¹ R² and R¹ and R²are loweralkyl or hydrogen have been shown to have low incidence ofantihistaminic, anticholinergic and cardiotoxic side effects when testedin animals.

The preferred pyridobenzodiazepines useful in the method of treatingdepression are as follows:

    ______________________________________                                        Example                                                                       No.       Compound active ingredient (free base)                              ______________________________________                                         9        N,N--dimethyl-6-phenyl-11H--pyrido[2,3-b][1,4]                                benzodiazepine-11-propanamine.                                      23        6-(4-fluorophenyl)-N,N--dimethyl-11H--pyrido                                  [2,3-b][1,4]benzodiazepine-11-propanamine.                          25        6-phenyl-11H--pyrido[2,3-b][1,4]benzodiazepine-                               11 propanamine.                                                     28        N--methyl-6-phenyl-11H--pyrido[2,3-b][1,4]                                    benzodiazepine-11-propanamine.                                       52b      6-(2-chlorophenyl)-N,N--dimethyl-11H--pyrido                                  [2,3-b][1,4]benzodiazepine-11-propanamine.                           52a      6-(2-fluorophenyl)-N,N--dimethyl-11H--pyrido                                  [2,3-b][1,4]benzodiazepine-11-propanamine.                          ______________________________________                                    

Compounds of the invention encompassed by Formula II which haveantidepressant activity in the foregoing procedure have the Formula IIp##STR13## wherein;

R is selected from the group consisting of hydrogen, loweralkyl or--alk¹ --NR¹ R² ;

R¹ and R² are selected from the group consisting of hydrogen,loweralkyl, --C(O)-loweralkyl or R¹ and R² taken together with theadjacent nitrogen atom may form a heterocyclic residue selected from thegroup consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl,4-morpholinyl, and 1-piperazinyl;

B is selected from carbonyl or thioxomethyl;

Ar, Z and Y are as defined under Formulas I and II above, and thepharmaceutically acceptable acid addition salts thereof.

The compounds of Formulas I and II wherein the R moiety carries aphthalimido, chloro, carbamoyl or imidate component are chemicalintermediates rather than antidepressant agents, and compounds ofFormula II wherein B is ketal or thioketal are also chemicalintermediates rather than antidepressants.

It is therefore an object of the present invention to provide novel6-aryl-11H-pyrido[1,4]benzodiazepines which have antidepressantactivity.

Another object is to provide novel [2-[(aminopyridinyl)amino]phenyl]arylmethanones and their thioxomethyl, ketal or thioketal analogs.

Another object is to provide methods of treating depression andpharmaceutical compositions therefor.

Still another object is to provide novel intermediates for preparingaryl substituted-11H-pyrido-[1,4]benzodiazepines which areantidepressants, certain of which intermediates also have antidepressantactivity.

Additional objects and advantages of the present invention will beapparent to one skilled in the art and others will be apparent from thefollowing description of the best mode of carrying out the presentinvention and from the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses the novel pyridobenzodiazepines andmethanone(thioxomethyl, ketal or thioketal analogs) intermediates as setforth herein in Formulas I and II as compositions of matter andutilization of these compounds as antidepressants or as intermediates inthe preparation of other antidepressants.

Description of Compound Preparation. Reaction sequence by equation forthe preparation of the compounds of the invention is given in Chart 1.Alternate procedures for preparation of certain of the compounds aregiven by equation in Charts 2, 3, 4, 5 and 6.

Methanones, Formula II, See Chart 1. The methanone (or analogs)intermediates are prepared by heating a mixture of the halo-aminopyridine and an aminobenzophenone (or analog) for a shorter period oftime than that required for cyclization to the pyridobenzodiazepine asindicated by chemical ionization mass spec. analysis. For the[2-[(3-amino-2-pyridinyl)amino]phenyl]methanones, the conditionsrequired are about 1 to 1.5 hr at 170°-200° C. The methanones andanalogs may be isolated as the predominant product, if desired, bycooling and adding a suitable organic solvent such as, for example,methylene chloride which will dissolve unreacted starting materials andsome cyclized compound (Ia) followed by usual methods of isolating suchas partitioning between the solvent and aqueous base or methanolicaqueous base followed by washing, drying, evaporating the solvent layerand recrystallizing from a suitable solvent.

Unsubstituted Pyridobenzodiazepines, Formulas Ia and Ia-1 (R=H), SeeChart 1. The purified II compounds or crude II compounds may be furtherheated in an aprotic solvent to cyclize to compounds of Formula Ia,removing water from the reaction mixture by conventional means; forexample under reflux using a Dean-Stark water trap. However, it is notnecessary to stop heating at the intermediate stage; generally, it issufficient to continue heating of the original reaction mixture, i.e.,III+IV, for a longer period of time during which cyclization to Iaoccurs. In the cyclization stage, whichever alternative is used, thetemperature time relationship will vary to some extent depending on thereactants used, it being only necessary to heat for a time sufficient toproduce the product desired as indicated by chemical ionization massspec. The unsubstituted pyridobenzodiazepines are purified bypartitioning between a suitable solvent such as methylene chloride andaqueous base, washing and drying the solvent layer, evaporating andchromatographing in a suitable solvent system such as acetone-benzene.The corresponding dihydrodiazepine may be prepared by reduction withsodium borocyanohydrin.

Substituted Pyridobenzodiazepines. Formulas Ib and Ib-1 (R=loweralkyl),See Chart 1. Preferably, compounds of Formula Ia (or Ia-1) wherein R ishydrogen are alkylated or alkylaminated or radicals are introduced whichwill lead to alkylamination by reacting first with sodium hydride andthen with an appropriate reagent represented by halo-alk¹ Q wherein"alk" has the meaning as defined above and Q is as defined in Chart 1.The compounds suspended in a suitable solvent such as dimethyl formamideare added to a stirred suspension of sodium hydride in the same solvent.The halo-alk¹ -Q reagent (alkylaminating agent or agent leading toalkylamination) is added at about room temperature and the reactionmixture is stirred for a period of time until reaction is complete as,for example, determined by thin layer chromatography. The unreactedsodium hydride is decomposed by adding to water and the product isextracted with a suitable solvent such as methylene chloride followed byaqueous acid extraction of the solvent layer and isolating the productfrom the aqueous layer by neutralization and re-extraction withmethylene chloride followed by evaporation and precipitating, preferablyas an addition salt such as fumarate, hydrochloride oxalate, maleate andthe like. Generally, once having obtained and purified an acid additionsalt, the free base may be regenerated by partitioning the salt betweenan aqueous base and a suitable solvent such as methylene chloride andevaporating the methylene chloride layer. The correspondingdihydrodiazepines may be prepared by reduction with sodiumborocyanohydrin. Alternately, compounds of Formulas Ib wherein Q is halomay be converted to compounds wherein Q is --N--(loweralkyl)₂ byreacting with an appropriate dialkylamine as given in the reactionsequence of Chart 2.

The primary amines of Formula Ic; i.e., R¹ and R² are both hydrogen, areprepared from the -alk¹ -ω-(1-phthalimido) derivatives, as shown inChart 1, by reacting with hydrazine hydrate, utilizing the method ofOrg. Syn. Coll. Vol. III, pp 151-153. Generally, about 2-3 hr refluxtime is sufficient after which aqueous acid is added and the mixture isfiltered. The primary -alk¹ -amines are isolated from suitable solventssuch as isopropyl alcohol. Hydrochlorides and hydrochloride hydrates arepreferred salts in the isolation step. The correspondingdihydrodiazepines may be obtained by reduction with sodiumborocyanohydrin.

The -alk¹ -ω-monoalkylamines (Formula Ie); e.g., R¹ =methyl, R²=hydrogen, may be prepared as shown in Chart 1 by reacting the primary--alk¹ --NH₂ derivatives Ic or Ic-1 with refluxing triethyl orthoformatefor a period of time sufficient to form the methanimidic acid ester(I-d) which is then reacted with sodium borohydride. The unreactedborohydride is decomposed with water and the product extracted out witha suitable solvent such as ethyl acetate and may be purified by columnchromatography and partitioning with basic solvent. Hydrochlorides arepreferred salts in the isolation step. The method is more fullyexemplified in Examples 27 and 28. The correspondingdihydrobenzodiazepines may then be prepared by reduction withsodium-borocyanohydrin.

-Alk¹ -ω-monomethylamines may also be prepared by reaction of theprimary amine with ethyl chloroformate as in Example 29, and thereafterreducing with lithium aluminum hydride as exemplified in Chart 3.

A further more generalized alternative for introduction of -alk¹-ω-monoloweralkyl amine radicals is via the radical: ##STR14## SeeCharts 1 and 4.

All formulas Ia, Ia-1, Ib, Ib-1, Ib-2, Ib-3, Ib-4, Ic, Ic-1, Ic-2, Id,Ie and Ie-1 are encompassed by Formula I.

Compounds of Formula I wherein the --NR¹ R² moiety is unsubstituted1-piperazinyl are obtained by hydrolizing a compound of Formula Iwherein --NR¹ R² is piperazino substituted in the 4-position by an alkylcarbonyl such as t-butoxycarbonyl.

Compounds of Formula II wherein R is hydrogen may be alkylaminated byreacting with sodium hydride and an appropriate reagent represented byhalo--alk¹ --NR¹ R² wherein "alk¹ " has the meaning as defined abovewith the proviso that R¹ and R² are not hydrogen. See Chart 5 for theequation. The addition and subsequent removal of blocking agents on theNH₂ radical on the pyridine ring is anticipated as a means of improvingyields. These compounds may then be cyclized to thepyrido[1,4]benzodiazepines.

Compounds of Formula II wherein B is carbonyl may also be prepared byhydrolyzing the appropriate pyrido[1,4]benzodiazepine with coldconcentrated hydrochloric acid. See Chart 6 for the equation. ##STR15##

The preparation of the novel[(amino-pyridinyl)amino-phenylaryl]methanones which are intermediates inthe preparation of the aryl substituted-pyrido[1,4]benzodiazepines areillustrated more fully in the following Intermediates 1 to 16.Structures of the intermediates are illustrated in Table 1. ##STR16##

PREPARATION OF METHANONE INTERMEDIATES Intermediate 1[2-[(3-Amino-2-pyridinyl)amino]phenyl]phenylmethanone

A stirred mixture of 39.4 g (0.20 mole) of2-amino]phenyl]phenylmethanone

A stirred mixture of 39.4 g (0.20 mole) of 2-aminobenzophenone and 28.3g (0.22 mole) of 3-amino-2-chloropyridine was heated at 180° C. undernitrogen atmosphere for 1.5 hr. The mixture was allowed to cool somewhatand 200 ml of methylene chloride was added slowly. After stirring for 3hr and standing overnight at room temperature, 40.1 g of solid wasfiltered off and recrystallized twice from methanolisopropyl ethergiving 4.3 g, presumably the hydrochloride salt; m.p. 187°-90° C. Thissolid was dissolved in a mixture of water-methanol, basified with 3Nsodium hydroxide and extracted with methylene chloride. The combinedmethylene chloride extracts were dried over magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromisopropyl ether (charcoal) to give 2.1 g of product; m.p. 91°-3° C.Drying prior to analysis was overnight at room temperature/0.02 mm Hg.

Analysis: Calculated for C₁₈ H₁₅ N₃ O: C,74.72; H,5.23; N,14.52. Found:C,74.94; H,5.23; N,14.69.

Intermediate 2[2-[(3-Amino-2-pyridinyl)amino]-4-chlorophenyl]phenylmethanone

A stirred mixture of 23.2 g (0.1 mole) of 2-amino-4'-chlorobenzophenoneand 14.2 g (0.11 mole) of 3-amino-2-chloropyridine was heated at 180° C.under nitrogen atmosphere for 2.5 hr. The mixture solidified uponcooling to room temperature and was broken up with a spatula. The solidwas suspended in 100 ml of methylene chloride and collected byfiltration. The filter cake was dissolved in a mixture ofwater-methanol, basified with 3N sodium hydroxide and extracted twicewith methylene chloride. The combined methylene chloride extracts weredried over magnesium sulfate and evaporated under reduced pressure. Theresidue which had crystallized was triturated in isopropyl ether and thesolid (16.7 g) collected by filtration. A 3 g sample was recrystallizedfrom isopropyl ether to give 1.6 g product;

m.p. 153°-155° C.

Analysis: Calculated for C₁₈ H₁₄ ClN₃ O: C,66.77; H,4.36; N,12.98.Found: C,67.06; H,4.36; N,13.17.

Intermediate 3[2-[(3-Amino-2-(pyridinyl)amino)phenyl](4-methylphenyl)methanone

A stirred mixture of 20.0 g (0.095 mole) of2-amino-4'-methylbenzophenone and 13.95 g (0.104 mole) of3-amino-2-chloropyridine (96%) was heated under a nitrogen atmosphere at180° C. for 2.0 hr. The mixture cooled to a glassy solid which wasbroken up, triturated in methylene chloride and the mixture stirredovernight. The solid was collected by filtration and dissolved in warmmethanol. The solution was basified with 3N sodium hydroxide, dilutedwith 500 ml of water and extracted 3 times with 250 ml of methylenechloride. The combined methylene chloride extracts were dried overmagnesium sulfate and evaporated under reduced pressure. The residuewhich crystallized on standing was recrystallized twice frombenzene-isooctane to give 4.2 g product, m.p. 126°-127.5° C.

Analysis: Calculated for C₁₉ H₁₇ N₃ O: C, 75.23; H, 5.65; N, 13.85.Found: C, 75.81; H, 5.69; N, 13.96.

Intermediate 4[2-[(3-Amino-2-pyridinyl)amino]-5-chlorophenyl]-(2-chlorophenyl)methanone

A stirred mixture of 20.0 g (0.156 mole) of 3-amino-2-chloropyridine and37.3 g (0.14 mole) of 2-amino-2',5-dichlorobenzophenone was heated at190° C. under nitrogen atmosphere for 5.5 hr. Thin layer chromatography(5% methyl alcohol-benzene on silica gel) indicated reaction had notsubstantially occurred. The mixture was stirred overnight at 190° C.,cooled somewhat, and 100 ml methylene chloride was added cautiously. Thesuspension was stirred for two hr and the black solid which formed wasseparated by filtration. The solid was suspended in 500 ml of methylenechloride and 300 ml of dilute sodium hydroxide was added. An emulsionformed and the mixture was filtered which allowed separation of layers.The methylene chloride layer was washed with two 250 ml portions ofwater by extraction, dried over magnesium sulfate and evaporated underreduced pressure. The residue was dissolved in benzene and filteredthrough a 300 g column of florisil to remove low R_(f) material. Allfractions were combined and evaporated under reduced pressure. Thinlayer chromatography showed presence of two major components with lowerR_(f) spot predominating. The residue was dissolved in benzene andchromatographed on a 600 g column of florisil packed in benzene. Thehigher R_(f) material was eluted with 1% acetone-benzene. Onevaporation, the residue was triturated in benzene and recrystallizedfrom benzene-isooctane to give 2.7 g product; m.p. 162°-4° C.

Analysis: Calculated for C₁₈ H₁₃ Cl₂ N₃ O: C,60.35; H,3.66; N, 11.73.Found: C, 60.67; H, 3.67; N, 11.77.

Intermediates 5a to 5u

Following the procedures of Intermediate 3 and substituting equal molaramounts of the following for 2-amino-4'-methylbenzophenone;

2-amino-4'-ethylbenzophenone,

2-amino-4'-isopropylbenzophenone,

2-amino-4'-bromobenzophenone,

2-amino-3'-fluorobenzophenone,

2-amino-4'-ethoxybenzophenone,

2-amino-4'-nitrobenzophenone,

2-amino-4'-trifluoromethylbenzophenone,

2-amino-3'-methylbenzophenone,

2-amino-3'-ethylbenzophenone,

2-amino-3'-methoxybenzophenone,

2-amino-3'-ethoxybenzophenone,

2-amino-2'-nitrobenzophenone,

2-amino-3'-trifluoromethylbenzophenone,

2-amino-2'-methylbenzophenone,

2-amino-2'-ethylbenzophenone,

2-amino-2'-methoxybenzophenone,

2-amino-2',4'-dichlorobenzophenone,

2-amino-3',4',5'-trimethoxybenzophenone,

2-amino-2'-fluorobenzophenone,

2-amino-2'-chlorobenzophenone, and

2-amino-2'-bromobenzophenone,

there are obtained:

(a) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-ethylphenyl)methanone,

(b) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-isopropylphenyl)methanone,

(c) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-bromophenyl)methanone,

(d) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-fluorophenyl)methanone,

(e) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-ethoxyphenyl)methanone,

(f) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-nitrophenyl)methanone,

(g)[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4trifluoromethylphenyl)methanone,

(h) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-methylphenyl)methanone,

(i) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-ethylphenyl)methanone,

(j) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-methoxyphenyl)methanone,

(k) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-ethoxyphenyl)methanone,

(l) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-nitrophenyl)methanone,

(m)[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-trifluoromethylphenyl)methanone,

(n) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-methylphenyl)methanone,

(o) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-ethylphenyl)methanone,

(p) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-methoxyphenyl)methanone,

(q)[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2,4-dichlorophenyl)methanone,

(r)[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3,4,5-trimethoxyphenyl)methanone,

(s) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-fluorophenyl)methanone,

(t) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-chlorophenyl)methanone,and

(u) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-bromophenyl)methanone.

Intermediates 6a to 6o

Following the procedure of Intermediate 2 and substituting equal molaramounts of the following for 2-amino-4-chlorobenzophenone:

2-amino-5-chlorobenzophenone,

2-amino-6-chlorobenzophenone,

2-amino-4-fluorobenzophenone,

2-amino-4-bromobenzophenone,

2-amino-4-trifluoromethylbenzophenone,

2-amino-4-methylbenzophenone,

2-amino-5-methylbenzophenone,

2-amino-6-methylbenzophenone,

2-amino-4-ethylbenzophenone,

2-amino-4-methoxybenzophenone,

2-amino-4-ethoxybenzophenone,

2-amino-4-nitrobenzophenone,

2-amino-5-nitrobenzophenone,

2-amino-3-methylbenzophenone, and

2-amino-3-chlorobenzophenone,

there are obtained:

(a) [2-[(3-amino-2-pyridinyl)amino]-5-chlorophenyl]phenylmethanone,

(b) [2[(3-amino-2-pyridinyl)amino]-6-chlorophenyl]phenylmethanone,

(c) [2-[(3-amino-2-pyridinyl)amino]-4-fluorophenyl]phenylmethanone,

(d) [2-[(3-amino-2-pyridinyl)amino]-4-bromophenyl]phenylmethanone,

(e)[2-[(3-amino-2-pyridinyl)amino]-4-trifluoromethylphenyl]phenylmethanone,

(f) [2-[(3-amino-2-pyridinyl)amino]-4-methylphenyl]phenylmethanone,

(g) [2-[(3-amino-2-pyridinyl)amino]-5-methylphenyl]phenylmethanone,

(h) [2-[(3-amino-2-pyridinyl)amino]-6-methylphenyl]phenylmethanone,

(i) [2-[(3-amino-2-pyridinyl)amino]-4-ethylphenyl]phenylmethanone,

(j) [2-[(3-amino-2-pyridinyl)amino]-4-methoxyphenyl]phenylmethanone,

(k) [2-[(3-amino-2-pyridinyl)amino]-4-ethoxyphenyl]phenylmethanone,

(l) [2-[(3-amino-2-pyridinyl)amino]-4-nitrophenyl]phenylmethanone,

(m) [2-[(3-amino-2-pyridinyl)amino]-5-nitrophenyl]phenylmethanone,

(n) [2-[(3-amino-2-pyridinyl)amino]-3-methylphenyl]phenylmethanone, and

(o) [2-[(3-amino-2-pyridindyl)amino]-3-chlorophenyl]phenylmethanone.

Intermediates 7a to 7c

Following the procedure of Intermediate 1 substituting equal molaramounts of the following for 3-amino-2-chloropyridine:

4-amino-3-chloropyridine,

3-amino-4-chloropyridine, and

2-amino-3-chloropyridine,

there are obtained:

(a) [2-[(4-amino-3-pyridinyl)amino]phenyl]phenylmethanone,

(b) [2-[(3-amino-4-pyridinyl)amino]phenyl]phenylmethanone, and

(c) [2-[(2-amino-3-pyridinyl)amino]phenyl]phenylmethanone.

Intermediate 8[2-[(3-Amino-2pyridinyl)amino]phenyl](3-chlorophenyl)methanone

A stirred mixture of 35 g (0.152 mole) of 2-amino-3'-chlorobenzophenoneand 23.4 g (0.182 mole) of 3-amino-2-chloropyridine was heated at 180°C. for 2 hr. The hot melt was allowed to cool to 110° C., after which100 ml of hot toluene was added dropwise with vigorous stirring. Themixture was allowed to cool while stirring to 30° C. and 50 ml ofmethylene chloride was added. After stirring for an additional 1/2 hour,the mixture was filtered and the filter cake suspended in methylenechloride with stirring for 1/2 hr and methylene chloride was separatedby filtration. The filter cake containing the product (25.4 g) waspartially dissolved in hot methanol (total volume 150 ml) and 50%aqueous sodium hydroxide was added until the mixture was basic. Icewater was added and the solution was extracted with methylene chloride.This methylene chloride extract was washed with water and dried overmagnesium sulfate and evaporated to dryness. The residue was dissolvedin isopropyl alcohol and boiled with charcoal. The mixture was filtered,reduced in volume to give a first crop of crystals weighing 16 g (33%).A portion of the crystals was recrystallized from isopropyl alcohol togive a brick red solid melting 119°-120° C.

Analysis: Calculated for: C,66.77; H,4.36; N,12.98. Found: C,66.78;H,4.42; N,12.94.

Intermediate 9[2-[(3-Amino-2-pyridinyl)amino]phenyl](4-fluorophenyl)methanone

A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenoneand 27 g (0.21 mole) of 3-amino-2-chloropyridine was heated at 175°-180°C. for 2.5 hr. The mixture was allowed to cool to 110° C., after which100 ml of hot toluene was added. On cooling to 50° C., 50 ml ofmethylene chloride was added. The solvent layer was decanted, leaving ablack solid mass which was dissolved in hot methanol. The solutionvolume was reduced by one half and allowed to stand overnight at roomtemperature. The mixture was filtered and the filter cake washed twiceby suspending in methylene chloride. The weight of crude solid producedwas 22.5 g. The solid was dissolved in methanol and basified with 50%aqueous sodium hydroxide. The mixture was extracted with methylenechloride and the extract dried and concentrated. The residue was twicecrystallized from isopropyl alcohol, decolorizing by boiling withcharcoal the second time, to give 14 g (28%) solid which was red-orangein color; m.p. 121.5°-122.5° C.

Analysis: Calculated for C₁₈ H₁₄ N₃ OF: C,70.35; H,4.59; N,13.67. Found:C,70.23; H,4.59 N,13.64.

Intermediate 10[2-[(3-Amino-2-pyridinyl)amino]phenyl](2-thienyl)methanone

In accordance with the procedure of Intermediate 9,(2-aminophenyl)(2-thienyl)methanone, prepared by the method of Steinkopf& Gunther, Ann. 522, 28-34 (1936), is reacted with3-amino-2-chloropyridine to give the title compound.

Intermediate 11[2-[(3-Amino-2-pyridinyl)amino]phenyl](3-thienyl)methanone

In accordance with the procedure of Intermediate 9,(2-aminophenyl)(3-thienyl)methanone is reacted with3-amino-2-chloropyridine to give the title compound.

Intermediate 12[2-[(3-Amino-2-pyridinyl)amino]phenyl](2-pyridinyl)methanone

The title compound is prepared by reacting(2-aminophenyl)(2-pyridinyl)methanone, as prepared by Schofield, K., J.Chem. Soc. 1949, 2408-12, with 3-amino-2-chloropyridine.

Intermediate 13[2-[(3-Amino-2-pyridinyl)amino]phenyl](3-pyridinyl)methanone

The title compound is prepared by reacting(2-aminophenyl)(3-pyridinyl)methanone as prepared by Abramovitch R. A. &Tertzakian, G., Tetrahedron Letters, 1963, 1511-15 and Abramovitch, R.A. et al., Can. J. Chem. 43(4), 725-31 (1965) with3-amino-2-chloropyridine.

Intermediate 14[2-[(3-Amino-2-pyridinyl)amino]phenyl](4-pyridinyl)methanone

The title compound is prepared by reacting(2-aminophenyl)(4-pyridinyl)methanone as prepared by Nann, A. J. andSchofield, K., J. Chem. Soc. 1952, 583-9 with 3-amino-2-chloropyridine.

Intermediates 15a to 15g

Following the procedure of Intermediate 1 and substituting equal molaramounts of the following for 3-amino-2-chloropyridine:

3-amino-2-chloro-4-methylpyridine,

3-amino-2-chloro-5-methylpyridine,

3-amino-2-chloro-6-methylpyridine,

3-amino-2-chloro-5,6-dimethylpyridine,

3-amino-2-chloro-6-methoxypyridine,

3-amino-4-chloro-2-methylpyridine, and

3-amino-2-chloro-5-methoxypyridine,

there are obtained:

(a) [2-[(3-amino-4-methyl-2-pyridinyl)amino]phenyl]phenylmethanone,

(b) [2-[(3-amino-5-methyl-2-pyridinyl)amino]phenyl]phenylmethanone,

(c) [2-[(3-amino-6-methyl-2-pyridinyl)amino]phenyl]phenylmethanone,

(d) [2-[(3-amino-5,6-dimethyl-2-pyridinyl)amino]phenyl]phenylmethanone,

(e) [2-[(3-amino-6-methoxy-2-pyridinyl)amino]phenyl]phenylmethanone,

(f) [2-[(3-amino-2-methyl-4-pyridinyl)amino]phenyl]phenylmethanone, and

(g) [2-[(3-amino-5-methoxy-2-pyridinyl)amino]phenyl]phenylmethanone.

Intermediates 16a to 16f

Following the procedure of Intermediate 1 and substituting equal molaramounts of the following for 3-amino-2-chloropyridine:

2-amino-3-chloro-5-methylpyridine,

2-amino-3-chloro-4,6-dimethylpyridine,

2-amino-3-chloro-5-ethylpyridine,

4-amino-3-chloro-5-methylpyridine,

4-amino-3-chloro-2,6-dimethylpyridine, and

4-amino-3-chloro-2-methylpyridine,

there are obtained:

(a) [2-[(2-amino-5-methyl-3-pyridinyl)amino]phenyl]phenylmethanone,

(b) [2-[(2-amino-4,6-dimethyl-3-pyridinyl)amino]phenyl]phenylmethanone,

(c) [2-[(2-amino-5-ethyl-3-pyridinyl)amino]phenyl]phenylmethanone,

(d) [2-[(4-amino-5-methyl-3-pyridinyl)amino]phenyl]phenylmethanone,

(e) [2-[(4-amino-6-methyl-3-pyridinyl)amino]phenyl]phenylmethanone, and

(f) [2-[(4-amino-2-methyl-3-pyridinyl]amino]phenyl]phenylmethanone.

Intermediate 17a-c

Following the procedure of Intermediate 1 and substituting equal molaramounts of the following for 2-aminobenzophenone and adding an inorganicbase to neutralize the acid formed:

(2-aminophenyl)phenylmethanethione,

2-(2-phenyl-1,3-dioxolan-2-yl)benzeneamine, and

2-(2-phenyl-1,3-dithiolan-2-yl)benzeneamine,

there are obtained

(a) [2-[3-amino-2-pyridinyl)amino]phenyl]phenylmethanethione,

(b) N² -[2-(2-phenyl-1,3-dioxolan-2-yl)phenyl]-2,3-pyridinediamine, and

(c) N² -[2-(2-phenyl-1,3-dithiolan-2-yl)phenyl]-2,3-pyridinediamine.

Intermediate 18[2-[(3-Amino-2-pyridinyl)-N-methylamino]phenyl]phenylmethanonehydrochloride

Following the procedure of Intermediate 1, 2-N-methylaminobenzophenoneis reacted with 3-amino-2-chloropyridine to give the title compound. Thefree base of the title compound is obtained also by the latter part ofthe procedure of Intermediate 1.

Intermediate 19[2-[(3-Amino-2-pyridinyl)-N-ethylamino]phenyl]phenylmethanonehydrochloride

Following the procedure of Intermediate 1, 2-N-ethylaminobenzophenone isreacted with 3-amino-2-chloropyridine to give the title compound. Thefree base of the title compound is obtained also by the latter part ofthe procedure of Intermediate 1.

Intermediate 20[2-[(3-Amino-2-pyridinyl)[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone

A solution ofN,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminein isopropyl alcohol is treated with 25% hydrochloric acid at 0° C. togive a solution of the title compound.

Intermediate 21[2-[[3-(Dimethylamino)propyl](3-amino-2-pyridinyl)amino]phenyl]phenylmethanone

To a stirred suspension of sodium hydride (in mineral oil) in anhydrousdimethylformamide, under nitrogen atmosphere was added, portionwise,[2-[(3-amino-2-pyridinyl)amino]phenyl]phenylmethanone. To the mixturewas added 3-dimethylaminopropyl chloride hydrochloride to give asolution containing some of the title compound as indicated by chemicalionization mass spectrascopy analysis. With time, this cyclizedspontaneously to the corresponding pyrido[2,3-b][1,4]benzodiazepine.

Intermediate 22[2-[(3-Amino-2-pyridinyl)[3-(3-dimethylamino)propyl]amino]phenyl]phenylmethione

To a stirred suspension of sodium hydride (in mineral oil) in anhydrousdimethylformamide under nitrogen atmosphere is added, portionwise,[2-[(3-amino-2-pyridinyl)amino]phenyl]phenylmethanethione. To themixture is added 3-dimethylaminopropyl chloride hydrochloride to give asolution containing the title compound.

Intermediate 23 N² -[3-(Dimethylamino)propyl]-N²-[2-(2-phenyl-1,3-dioxolan-2-yl)phenyl]-2,3-pyridinediamine

To a stirred suspension of sodium hydride (in mineral oil) in anhydrousdimethylformamide under nitrogen atmosphere is added, portionwise, N²-[2-(2-phenyl-1,3-dioxolan-2-yl)phenyl]-2,3-pyridinediamine. To themixture is added 3-dimethylaminopropyl chloride hydrochloride to give asolution containing the title compound.

Intermediate 24 N² -[3-(Dimethylamino)propyl]-N²-[2-(2-phenyl-1,3-dithiolan-2-yl)phenyl]-2,3-pyridinediamine

To a stirred suspension of sodium hydride (in mineral oil) in anhydrousdimethylformamide under nitrogen atmosphere is added, portionwise, N²-[2-(2-phenyl-1,3-dithiolan-2-yl)phenyl]-2,3-pyridinediamine. To themixture is added 3-dimethylaminopropyl chloride hydrochloride to give asolution containing the title compound.

                                      TABLE 1                                     __________________________________________________________________________    Inter-                                                                        mediate                                                                            Ar          B     Y     R      Z                                         __________________________________________________________________________     ##STR17##                                                                    1    C.sub.6 H.sub.5                                                                           C(O)  H     H      H                                         2    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-Cl                                      3    4-CH.sub.3C.sub.6 H.sub.4                                                                 C(O)  H     H      H                                         4    2-ClC.sub.6 H.sub.4                                                                       C(O)  H     H      5-Cl                                      5a   4-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                          C(O)  H     H      H                                         b    4-i-C.sub.3 H.sub.7C.sub.6 H.sub.4                                                        C(O)  H     H      H                                         c    4-BrC.sub.6 H.sub.4                                                                       C(O)  H     H      H                                         d    3-FC.sub.6 H.sub.4                                                                        C(O)  H     H      H                                         e    4-OC.sub.2 H.sub.5C.sub.6 H.sub.4                                                         C(O)  H     H      H                                         f    4-NO.sub.2C.sub.6 H.sub.4                                                                 C(O)  H     H      H                                         g    4-CF.sub.3C.sub.6 H.sub.4                                                                 C(O)  H     H      H                                         h    3-CH.sub.3C.sub.6 H.sub.4                                                                 C(O)  H     H      H                                         i    3-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                          C(O)  H     H      H                                         j    3-OCH.sub.3C.sub.6 H.sub.4                                                                C(O)  H     H      H                                         k    3-OC.sub.2 H.sub.5C.sub.6 H.sub.4                                                         C(O)  H     H      H                                         l    2-NO.sub.2C.sub.6 H.sub.4                                                                 C(O)  H     H      H                                         m    3-CF.sub.3C.sub.6 H.sub.4                                                                 C(O)  H     H      H                                         n    2-CH.sub.3C.sub.6 H.sub.4                                                                 C(O)  H     H      H                                         o    2-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                          C(O)  H     H      H                                         p    2-OCH.sub.3C.sub.6 H.sub.4                                                                C(O)  H     H      H                                         q    2,4-Cl.sub.2C.sub.6 H.sub.3                                                               C(O)  H     H      H                                         r    3,4,5-(OCH.sub.3).sub.3C.sub.6 H.sub.2                                                    C(O)  H     H      H                                         s    2-FC.sub.6 H.sub.4                                                                        C(O)  H     H      H                                         t    2-ClC.sub.6 H.sub.4                                                                       C(O)  H     H      H                                         u    2-BrC.sub.6 H.sub.4                                                                       C(O)  H     H      H                                         6a   C.sub.6 H.sub.5                                                                           C(O)  H     H      5-Cl                                      b    C.sub.6 H.sub.5                                                                           C(O)  H     H      6-Cl                                      c    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-F                                       d    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-Br                                      e    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-CF.sub.3                                f    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-Me                                      g    C.sub.6 H.sub.5                                                                           C(O)  H     H      5-Me                                      h    C.sub.6 H.sub.5                                                                           C(O)  H     H      6-CH.sub.3                                i    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-C.sub.2 H.sub.5                         j    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-OCH.sub.3                               k    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-OC.sub.2 H.sub. 5                       l    C.sub.6 H.sub.5                                                                           C(O)  H     H      4-NO.sub.2                                m    C.sub.6 H.sub.5                                                                           C(O)  H     H      5-NO.sub.2                                n    C.sub.6 H.sub.5                                                                           C(O)  H     H      3-CH.sub.3                                o    C.sub.6 H.sub.5                                                                           C(O)  H     H      3-Cl                                      8    3-ClC.sub.6 H.sub.4                                                                       C(O)  H     H      H                                         9    4-FC.sub.6 H.sub.4                                                                        C(O)  H     H      H                                         10   2-thienyl   C(O)  H     H      H                                         11   3-thienyl   C(O)  H     H      H                                         12   2-pyridinyl C(O)  H     H      H                                         13   3-pyridinyl C(O)  H     H      H                                         14   4-pyridinyl C(O)  H     H      H                                         15a  C.sub.6 H.sub.5                                                                           C(O)  4-CH.sub.3                                                                          H      H                                         15b  C.sub.6 H.sub.5                                                                           C(O)  5-CH.sub.3                                                                          H      H                                         15c  C.sub.6 H.sub.5                                                                           C(O)  6-CH.sub.3                                                                          H      H                                         15d  C.sub.6 H.sub.5                                                                           C(O)  5,6-(CH.sub.3).sub.2                                                                H      H                                         15e  C.sub.6 H.sub.5                                                                           C(O)  6-OCH.sub.3                                                                         H      H                                         15g  C.sub.6 H.sub.5                                                                           C(O)  5-OCH.sub.3                                                                         H      H                                         17a  C.sub.6 H.sub.5                                                                           C(S)  H     H      H                                         b    C.sub.6 H.sub.5                                                                            ##STR18##                                                                          H     H      H                                         c    C.sub.6 H.sub.5                                                                            ##STR19##                                                                          H     H      H                                         18   C.sub.6 H.sub.5                                                                           C(O)  H     CH.sub.3                                                                             H                                         19   C.sub.6 H.sub.5                                                                           C(O)  H     C.sub.2 H.sub.5                                                                      H                                         20   C.sub.6 H.sub.5                                                                           C(O)  H     (CH.sub.2).sub.3 N                                                                   H                                                                      (CH.sub.3).sub.2                                 21   C.sub.6 H.sub.5                                                                           C(O)  H     (CH.sub.2).sub.3 N                                                                   H                                                                      (CH.sub.3).sub.2                                 22   C.sub.6 H.sub.5                                                                           C(S)  H     (CH.sub.2).sub.3 N                                                                   H                                                                      (CH.sub.3).sub.2                                 23   C.sub.6 H.sub.5                                                                            ##STR20##                                                                          H     (CH.sub.2).sub.3 N (CH.sub.3).sub.2                                                  H                                         24   C.sub.6 H.sub.5                                                                            ##STR21##                                                                          H     (CH.sub.2).sub.3 N (CH.sub.3).sub.2                                                  H                                          ##STR22##                                                                    7a   C.sub.6 H.sub.5                                                                           C(O)  H     H      H                                         16d  C.sub.6 H.sub.5                                                                           C(O)  5-CH.sub.3                                                                          H      H                                         e    C.sub.6 H.sub.5                                                                           C(O)  6-CH.sub.3                                                                          H      H                                         f    C.sub.6 H.sub.5                                                                           C(O)  2-CH.sub.3                                                                          H      H                                          ##STR23##                                                                    7b   C.sub.6 H.sub.5                                                                           C(O)  H     H      H                                         15f  C.sub.6 H.sub.5                                                                           C(O)  2-CH.sub.3                                                                          H      H                                          ##STR24##                                                                    7c   C.sub.6 H.sub.5                                                                           C(O)  H     H      H                                         16a  C.sub.6 H.sub.5                                                                           C(O)  5-CH.sub.3                                                                          H      H                                         b    C.sub.6 H.sub.5                                                                           C(O)  4,6(CH.sub.3).sub.2                                                                 H      H                                         c    C.sub.6 H.sub.5                                                                           C(O)  5-C.sub.2 H.sub.5                                                                   H      H                                         __________________________________________________________________________

The preparation of novel phenyl-substituted pyrido[1,4]benzodiazepinecompounds of the present invention and the novel process is exemplifiedmore fully by the following examples. Structures of the compounds of theexamples are illustrated in Table 2. The scope of the invention is notlimited thereto, however.

EXAMPLE 1 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine

A mixture of 19.7 g (0.1 mole) of 2-aminobenzophenone and 15.0 g (0.12mole) of 3-amino-2-chloropyridine was heated under nitrogen atmosphereat 190° C. for 1.75 hr. The mixture was cooled to room temperature andpartitioned between 3N aqueous sodium hydroxide and methylene chloride.The combined methylene chloride extracts were washed with water, driedover magnesium sulfate and evaporated under reduced pressure. Theresidue, 32.7 g, was dissolved in benzene and chromatographed on acolumn of florisil packed in benzene, eluting with benzene and 1-2%acetone-benzene mixtures. After evaporation, the solid was crystallizedfrom benzene to give 7.3 g product; m.p. 106°-108° C.

Analysis: Calculated for C₁₈ H₁₃ N₃ : C,79.68; H,4.83; N,15.49. Found:C,79.70; H,4.81; N,15.42.

EXAMPLE 2 8-Chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine

A mixture of 15.0 g (0.0647 mole) of 2-amino-5-chlorobenzophenone and9.1 g (0.068 mole) of 3-amino-2-chloropyridine was heated at 200° C. (inan oil bath) for 0.75 hr under nitrogen atmosphere. The mixture wascooled and methylene chloride added. The mixture was stirred for 1 hrthen allowed to stand overnight. Brown solid precipitate weighing 8.7 gwas separated by filtration. The filtrate was evaporated under reducedpressure. The residue was combined with the brown solid and partitionedwith aqueous sodium hydroxide and methylene chloride and crude productisolated as in Example 1, except the crystallizing solvent was ethanol.Recrystallization from ethanol and drying over night at 82° C./0.1 mm Hggave 3.0 g product; m.p. 156.5°-158.5° C.

Analysis: Calculated for C₁₈ H₁₂ ClN₃ : C,70.71; H,3.96; N,13.74. Found:C,70.24; H,4.01; N,13.76.

EXAMPLE 3 9-Chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine

A suspension of 6.6 g (0.02 mole) of[2-[(3-amino-2-pyridyl)amino]-4-chlorophenyl]-(phenyl)methanone(Intermediate 2) in 200 ml of toluene was heated at reflux over nightunder nitrogen atmosphere. The reaction mixture was filtered hot and thefiltrate heated back to reflux temperature. The precipitate formed incooling to room temperature was separated by filtration andrecrystallized from benzene and dried 4 hr at 97°-98° C./0.1 mm Hg andover night at room temperature/0.1 mm Hg to give 3.7 g; m.p. 250.5° to252° C. Elemental analysis for carbon was high and the product wasredried at 139° C. (xylenes in drying pistol) for 8 hr. Although thecarbon analysis remained high, the proton nuclear magnetic resonancespectrum and mass spectrum was consistent with the proposed structure.

Analysis: Calculated for C₁₆ H₁₂ ClN₃ : C,70.71; H,3.96; N,13.74. Found:C,71.46; H,4.06; N,13.46.

EXAMPLE 48-Chloro-6-(2-chlorophenyl)-5,6-dihydro-11H-pyrido[2,3-b][1,4]benzodiazepin

Further elution of the florisil column in the preparation ofIntermediate 4 with 10-15% acetone in benzene and 5-25% methanol inbenzene gave two fractions of the title product of this example, 6.4 gand 5.7 g, the second being quite impure. The 6.4 g fraction wasrecrystallized from benzene-isooctane to give 3.7 g of solid; m.p.203°-6° C. (decomposition) which was identified by chemical ionizationmass spec. analysis, ¹ H and ¹³ C NMR as8-chloro-6-(2-chlorophenyl)-5,6-dihydro-11H-pyrido[2,3-b][1,4]benzodiazepine.

EXAMPLE 5 6-(4-Chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

A mixture of 23.2 g (0.10 mole) of 2-amino-4'-chlorobenzophenone and14.7 g (0.11 mole) of 3-amino-2-chloropyridine (96%) were heated for 1.5hr at 180° C. under nitrogen atmosphere. The mixture was cooled to roomtemperature and methylene chloride added. After stirring for 30 min.,solids were separated by filtration and triturated in hot 190 proofethanol. The remaining insoluble material was collected by filtrationand recrystallized from benzene-isooctane to give 2.7 g product, m.p.203°-204.5° C. Drying conditions prior to analyses were: overnight at97°-98° C./0.1 mm Hg.

Analysis: Calculated for C₁₈ H₁₂ ClN₃ : C,70.71; H,3.96; N,13.74. Found:C,70.76; H,3.92; N,13.95.

EXAMPLE 6 6-(4-Methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

A solution of 3.6 g (0.012 mole) of[2-[(3-amino-2-pyridyl)amino]phenyl](4-methylphenyl)methanone in 100 mlof anhydrous toluene was treated with a catalytic amount of para toluenesulfonic acid and refluxed overnight while separating water with aDean-Stark trap. The reaction mixture was filtered while hot. Theproduct precipitated as the filtrate cooled to room temperature and wascollected by filtration. Weight of solid after solvent evaporated was2.5 g, m.p. 203.5°-205° C. (decomp.).

Analysis: Calculated for C₁₉ H₁₅ N₃ : C,79.98; H,5.30; N,14.73. Found:C,79.95; H,5.27; N,14.76.

EXAMPLE 7 6-(4-Methoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

A stirred mixture of 20.0 g (0.088 mole) of2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mole) of3-amino-2-chloropyridine (96%) was heated at 180° C. under a nitrogenatmosphere for 2.0 hr. The reaction mixture was cooled to approximately70° C. and 100 ml of methylene chloride was added slowly. After themixture had cooled to room temperature, another 50 ml of methylenechloride was added and the mixture was stirred overnight. The suspendedsolid was collected by filtration, air dried, dissolved in methanol andbasified with 3N sodium hydroxide. The suspension was diluted with 500ml water and extracted with three 250 ml portions of methylene chloride.The combined methylene chloride extracts were dried over magnesiumsulfate and evaporated under reduced pressure. Analysis by mass spectra(EI and CI) indicated the residue was a mixture of[2-[(3-amino-2-pyridyl)amino]phenyl](4-methoxyphenyl)methanone and thetitle compound. The residue-mixture was dissolved in 250 ml toluene witha catalytic amount of para toluene sulfonic acid and the solution wasrefluxed overnight under a nitrogen atmosphere while separating water ina Dean-Stark trap. The reaction mixture was filtered while hot. Theproduct precipitated as the filtrate cooled to room temperature and wascollected by filtration. After recrystallization from benzene theproduct weighed 1.8 g, m.p. 198.5°-200.5° C. (d).

Analysis: Calculated for C₁₉ H₁₅ N₃ O: C,75.73; H,5.02; N,13.94. Found:C,75.65; H,4.98; N,14.03.

EXAMPLE 88-Chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamineoxalate [1:1]

To a stirred suspension of 1.05 g (0.044 mole) of sodium hydride (inmineral oil) in 50 ml of anhydrous dimethylformamide, under nitrogenatmosphere was added, portionwise, 6.1 g (0.02 mole) of8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reactionmixture was stirred at room temperature for 1.5 hr, during whichevolution of hydrogen ceased. To the mixture was added, portionwise, 3.5g (0.022 mole) of 3-dimethylaminopropylchloride hydrochloride. Afterstirring overnight at room temperature, the reaction mixture was pouredinto 1600 ml water and the combination extracted with three 250 mlportions of methylene chloride. The combined methylene chloride extractwas washed with two 250 ml portions of water, dried over magnesiumsulfate and evaporated under reduced pressure. The residue was dissolvedin benzene and chromatographed with acetone-benzene on a 300 g column offlorisil packed in benzene. Starting material, 1.6 g., was recovered inthe benzene elution and 3.6 g. containing the product as free base wasobtained from the acetone-benzene elution on evaporation of solvent. Aportion of the crude free base, 2.5 g., was dissolved in hot isopropylalcohol and reacted with 0.8 g (0.0064 mole) of oxalic acid dihydrate.The oxalate salt, which precipitated on cooling, was collected byfiltration and recrystallized from ethanol to give 2.2 g product, m.p.206°-208° C. Drying conditions prior to analyses were: 5 hr at 97°-98°C./0.02 mm Hg; over night at room temperature/0.02 mm Hg.

Analysis: Calculated for C₂₅ H₂₅ ClN₄ O₄ : C,62.43; H,5.24; N,11.65.Found: C,62.52; H,5.23; N,11.76.

EXAMPLE 9N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate [1:1]

To a stirred suspension of 1.68 g (0.070 mole) of sodium hydride (inmineral oil) in 25 ml of anhydrous dimethylformamide, under nitrogenatmosphere, was added, portionwise, a suspension of 8.0 g (0.029 mole)of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine in 20 ml of anhydrousdimethylformamide. The mixture was stirred for 30 min after addition wascomplete, warmed to 65° C. for 15 min and cooled again to roomtemperature. To the mixture was added 5.6 g (0.035 mole) of3-dimethylaminopropyl chloride hydrochloride. After stirring overnightat room temperature, thin-layer chromatography indicated the reactionwas nearly complete. The reaction mixture was poured into 1500 ml waterand extracted with 250 ml of methylene chloride. The methylene chlorideextract was washed with three 250 ml portions of water, dried overmagnesium sulfate and evaporated under reduced pressure. The residue wasdissolved in methylene chloride and extracted with 100 ml and 150 mlportions of 3N hydrochloric acid. Unreacted6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine starting materialprecipitated from the aqueous acidic solution and was separated bycarefully decanting the liquid from the solid. The aqueous solution wasbasified with 3N sodium hydroxide and extracted with three 100 mlportions of methylene chloride. The combined methylene chloride extractswere dried over magnesium sulfate and evaporated under reduced pressureto give 7.7 g residue, the free base of the title compound. A solutionof 6.6 g of the residue in hot isopropyl alcohol was reacted with 2.15 gof fumaric acid and the mixture heated until dissolution was completed.On standing for 48 hr, the salt which had precipitated was collected byfiltration. After recrystallization from isopropyl alcohol-isopropylether, 5.9 g of product was obtained, m.p. 171°-173° C. Dryingconditions prior to analyses were: 4 hr at 90° C./0.1 mm Hg; overnightat room temperature/0.1 mm Hg.

Analysis: Calculated for C₂₇ H₂₈ N₄ O₄ : C,68.63; H,5.97; N,11.86.Found: C,68.37; H,6.05; N,11.73.

EXAMPLE 10N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepin-11-ethanaminefumarate [1:1]

To a stirred suspension of 1.48 g (0.062 mole) of sodium hydride (inmineral oil) in 35 ml of anhydrous dimethylformamide, under nitrogenatmosphere, was added, portionwise, 7.0 g (0.026 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. After cooling thereaction mixture to room temperature, 4.46 g (0.031 mole) of2-dimethylaminoethyl chloride hydrochloride was added portionwise andstirring continued overnight. The reaction mixture was poured into 1500ml of water and the resultant mixture extracted with 250 ml of methylenechloride. The methylene chloride extract was washed with three 500 mlportions of water, dried over magnesium sulfate and evaporated underreduced pressure to give 8.6 g of an oil, the free base of the titlecompound. Part of the oil, 6.9 g, was reacted with an equal molar amountof fumaric acid in isopropyl alcohol. Addition of isopropyl ether gavean oily solid. The mixture was evaporated under reduced pressure and theresidue crystallized on standing. The crystals were triturated withacetone and recrystallized from acetone-isopropyl ether to give 4.3 g ofthe fumarate salt, m.p. 175°-177.5° C.

Analysis: Calculated for C₂₆ H₂₆ N₄ O₄ : C,68.11; H,5.72; N,12.22.Found: C,67.88; H,5.72; N,12.17.

EXAMPLE 1111-[3-(4-Morpholinyl)propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepinefumarate [1:1]

To a stirred suspension of 1.10 g (0.046 mole) of sodium hydride (inmineral oil) in 25 ml of anhydrous dimethylformamide under nitrogenpresssure was added, portionwise, 5.0 g (0.0184 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture wasstirred at room temperature for 15 min, warmed at 65°-70° C., for 10 minand allowed to cool to room temperature. To the mixture was added,portionwise, 4.1 g (0.02 mole) of 4-(3-chloropropyl)morpholinehydrochloride. The reaction mixture was stirred at room temperature for16 hr and then poured into 800 ml of water. This mixture was extractedtwice with 200 ml portions of methylene chloride. The combined methylenechloride extracts were extracted with 150 ml and 75 ml portions of 3Nhydrochloric acid and the combined aqueous extracts were basified with3N sodium hydroxide. The resulting suspension was extracted with two 150ml portions of methylene chloride and these latter two extractscombined, dried over magnesium sulfate and evaporated under reducedpressure. The residue, the free base of the title compound, was reactedwith an equal molar amount of fumaric acid in warm isopropyl alcohol andthe mixture treated with isopropyl ether. The fumarate salt wascollected by filtration and recrystallized from ethanol-ethyl acetate togive 5.6 g, m.p. 154°-7° C. Drying conditions prior to analyses were: 4hr at 97°-98° C./0.1 mm Hg; overnight at room temperature/0.1 mm Hg.

Analysis: Calculated for C₂₉ H₃₀ N₄ O₅ : C,67.69; H,5.88; N,10.88.Found: C,67.52; H,5.84; N,10.90.

EXAMPLE 12N,N-Diethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamineoxalate [1:1]

To a stirred suspension of 1.10 g (0.0461 mole) of sodium hydride (inmineral oil) in 25 ml of anhydrous dimethylformamide under nitrogenatmosphere was added, portionwise, 5.0 g (0.0184 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture wasstirred at room temperature for 0.5 hr, warmed to 65°-70° C. and cooledslowly to room temperature. To the mixture was added, portionwise, 3.77g (0.020 mole) of 3-diethylaminopropylchloride hydrochloride and thereaction mixture stirred at room temperature for 16 hr. The mixture waspoured into 750 ml of water and extracted with three 150 ml portions ofmethylene chloride. The combined methylene chloride extracts wereextracted with 150 ml and 75 ml portions of 3N hydrochloric acid. Thecombined aqueous extracts were basified with 3N sodium hydroxide andthen extracted with three 100 ml portions of methylene chloride. Thecombined methylene chloride extracts were dried over magnesium sulfateand evaporated under reduced pressure to give 7.5 g of the free base ofthe title compound. A portion, 5.6 g, was reacted with an equal molaramount of oxalic acid dihydrate in hot isopropyl alcohol. The oxalatesalt was collected by filtration to give 5.5 g product, m.p. 196°-199°C. Drying conditions prior to analyses were: 1 hr at 97°-98° C./0.1 mmHg.

Analysis: Calculated for C₂₇ H₃₀ N₄ O₄ : C,68.34; H,6.37; N,11.81.Found: C,68.31; H,6.43; N,11.86.

EXAMPLE 139-Chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate [1:1]

To a stirred suspension of 0.98 g (0.041 mole) of sodium hydride (inmineral oil) in 25 ml of anhydrous dimethylformamide under nitrogenatmosphere was added, portionwise, 5.0 g (0.016 mole) of9-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine over a 45 minperiod. The reaction mixture was stirred at room temperature for 1 hr,warmed to 70° C. and then cooled slowly to room temperature. To themixture was added, portionwise, over a 30 min period, 2.84 g (0.018mole) of 3-dimethylaminopropyl chloride hydrochloride and the reactionmixture stirred at room temperature for 17 hr. The mixture was pouredinto 750 ml water and extracted with 150 ml and two 100 ml portions ofmethylene chloride. The combined methylene chloride extracts were washedwith two 100 ml portions of water followed by extraction with 100 ml and75 ml portions of 3N hydrochloric acid. The acidic extracts werecombined and filtered to remove precipitate which had formed and thefiltrate was basified with 3N sodium hydroxide and extracted with three100 ml portions of methylene chloride. The combined methylene chlorideextracts were dried over magnesium sulfate and evaporated under reducedpressure. The residue was dissolved in methylene chloride and filteredthrough a 50-60 g bed of florisil in a sintered glass funnel. The bedwas washed in succession with 1%, 2%, 3% and 5% methanol-methylenechloride mixtures, the filtrates combined and evaporated under reducedpressure to give the free base of the title compound. The free base wasreacted with an equal molar amount of fumaric acid in hot isopropanol togive 3.3 g fumarate, m.p. 199°-202° C.

Analysis: Calculated for C₂₇ H₂₇ N₄ O₄ Cl: C,63.96; H,5.37; N,11.05.Found: C,63.63; H,5.36; N,11.00.

EXAMPLE 146-Phenyl-11-[3-(1-piperidinyl)propyl]-11H-pyrido[2,3-b][1,4]benzodiazepinefumarate [1:1]

To a stirred suspension of 1.10 g (0.0461 mole) of sodium hydride (inmineral oil) in 25 ml of anhydrous dimethylformamide under nitrogenatmosphere was added, portionwise, 5.0 g (0.018 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture wasstirred for 30 min, warmed to 70° C. and cooled to room temperature. Tothe mixture was added, portionwise, 4.14 g (0.0203 mole) ofN-(3-chloropropyl)piperidine hydrochloride and the reaction mixture wasstirred at room temperature for 16 hr. The mixture was poured into 750ml of water, extracted with 150 ml methylene chloride by stirring for 15min. The aqueous layer was extracted with two additional 100 ml portionsof methylene chloride. The combined methylene chloride extracts wereextracted with 150 ml and 75 ml portions of 3N hydrochloric acid and thecombined acid extracts basified with 3N sodium hydroxide and thenextracted with three 100 ml portions of methylene chloride. Themethylene chloride extracts were combined, dried over magnesium sulfateand evaporated under reduced pressure. The residue was dissolved in aminimum of methylene chloride and filtered through a 100 g bed offlorisil in a sintered glass funnel. The bed was washed successivelywith methylene chloride, 1%, 2%, 3% and 5% methanol-methylene chloridemixtures. All the filtrates were combined and evaporated under reducedpressure. The residue was reacted with 1.3 g fumaric acid in hotisopropanol and isopropyl ether added. An amorphous precipitate wasformed. The entire mixture was evaporated to dryness and the residuedissolved in 200 ml of ethanol. The solution was warmed to reflux,filtered and isopropyl ether added to the filtrate. Crystals whichformed overnight were filtered off to give 4.1 g fumarate salt, m.p.153°-6° C. Drying conditions prior to analyses were: 4 hr at 97°-98°C./0.1 mm Hg.

Analysis: Calculated for C₃₀ H₃₂ N₄ O₄ : C,70.29; H,6.29; N,10.93.Found: C,70.38; H,6.32; N,10.92.

EXAMPLE 156-(4-Chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate [1:1]

To a stirred suspension of 1.57 g (0.065 mole) of sodium hydride (inmineral oil) in 25 ml of anhydrous dimethylformamide was added undernitrogen atmosphere, 8.0 g (0.026 mole) of6-(4-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine. The reactionmixture was stirred for 1 hr at room temperature, warmed at 80° C. for15 min and cooled to room temperature. To the mixture was added,portionwise, 4.55 g (0.029 mole) of 3-dimethylaminopropyl chloridehydrochloride and the mixture was stirred overnight at room temperature.The mixture was poured into 750 ml of water and stirred for 30 min with150 ml of methylene chloride. The aqueous layer was extracted furtherwith three 100 ml portions of methylene chloride. The combined methylenechloride extracts were dried over magnesium sulfate and evaporated underreduced pressure to give the free base of the title compound. The freebase was reacted with an equal molar amount of fumaric acid in hotisopropanol. On cooling, 3.6 g of the fumarate salt precipitated, m.p.200.5°-202.5° C. The product was air dried further prior to analysis.

Analysis: Calculated for C₂₇ H₂₇ ClN₄ O₄ : C,63.96; H,5.37; N,11.05.Found: C,64.18; H,5.33; N,11.07.

EXAMPLE 168-Chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepin-11-ethanamineoxalate [1:1]

To a stirred suspension of 1.05 g (0.044 mole) of sodium hydride (inmineral oil) in 50 ml of anhydrous dimethylformamide was added,portionwise, 6.1 g (0.02 mole) of8-chloro-6-phenyl-11H-pyrido[2,3-b]benzodiazepine. The reaction mixturewas stirred at room temperature for 1.5 hr, during which time evolutionof hydrogen ceased. The reaction mixture was cooled to 5° C. and 3.2 g(0.022 mole) of 2-dimethylaminoethyl chloride hydrochloride was added,portionwise, followed by stirring at room temperature for about 60 hr.The reaction mixture was poured into 1600 ml of water and the mixtureextracted three times with 500 ml portions of methylene chloride. Thecombined extracts were washed with two 500 ml portions of water, driedover magnesium sulfate and evaporated under reduced pressure. Thin layerchromatography (20% methanol/benzene on silica gel) indicated thepresence of free base of the title compound and of starting material.The residue was dissolved in benzene and chromatographed on a 200 gcolumn of florisil packed in benzene. Starting material, 1.3 g of8-chloro-6-phenyl-11H-pyrido[2,3-b]1,4]benzodiazepine was eluted withbenzene and the free base of the title compound was eluted with mixturesof acetone in benzene. The free base was reacted with an equal molaramount of oxalic acid dihydrate in refluxing isopropyl alcohol andproduct recrystallized from isopropyl alcohol weighed 1.6 g, m.p.228.5°-232° C. Drying conditions prior to analysis were 6 hr at 82°C./0.1 mm Hg; overnight at room temperature.

Analysis: Calculated for C₂₄ H₂₃ ClN₄ O₄ : C,61.74; H,4.96; N,12.00.Found: C,61.62; H,4.95; N,11.98.

EXAMPLE 178-Chloro-11-methyl-6-phenyl-11H-pyrido[2,3-b[1,4]benzodiazepine

To a stirred suspension of 0.25 g (0.01 mole) of sodium hydride (inmineral oil) in 15 ml of anhydrous dimethylformamide was added,portionwise, 3.05 g (0.01 mole) of8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The mixture waswarmed at about 60° C. for one hr. A solution of 1.42 g (0.01 mole) ofmethyl iodide in 10 ml of anhydrous dimethylformamide was added dropwiseover a 0.5 hr period and the reaction mixture stirred overnight at roomtemperature after which it was poured into 400 ml of water and stirredfor 2 hr. The precipitated solid was recrystallized twice from isopropylalcohol to give 2.0 g of product, m.p. 153°-6° C. Drying conditionsprior to analyses were 1 hr at 82° C./0.1 mm Hg.

Analysis: Calculated for C₁₉ H₁₄ ClN₃ : C,71.36; H,4.41; N,13.14. Found:C,71.64; H,4.43; N,13.32.

EXAMPLE 18N,N-Dimethyl-6-(4-methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate [1:1]

To a stirred suspension of 0.51 g (0.022 mole) of sodium hydride in 25ml of anhydrous dimethylformamide under nitrogen atmosphere was added,portionwise, 4.2 g (0.0147 mole) of6-(4-methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine over a 45 minperiod. The mixture was stirred for 1 hr at room temperature, warmed at75°-80° C. for 1 hr, cooled to room temperature and a solution of 0.0184mole of 3-dimethylaminopropyl chloride in 10 ml of anhydrousdimethylformamide was added dropwise. The mixture was stirred overnightat room temperature and poured into 1000 ml of water. The suspension wasextracted with three 150 ml portions of methylene chloride and thecombined methylene chloride extracts were extracted with two 150 mlportions of 3N hydrochloric acid. A precipitate formed in the acidicsolution which was removed by filtration and discarded. The filtrate wasbasified with 3N NaOH and extracted with three 100 ml portions ofmethylene chloride. The combined methylene chloride extracts were driedover magnesium sulfate and evaporated under reduced pressure to give anoil, the free base of the title compound. This residual oil wasdissolved in hot isopropyl alcohol and reacted with an equal molaramount of fumaric acid. The fumarate salt crystallized as the solutioncooled to room temperature and was recrystalllized twice from isopropylalcohol-isopropyl ether to give 1.7 g product, m.p. 187°-189° C.,(decomp.).

Analysis: Calculated for C₂₈ H₃₀ N₄ O₄ : C,69.12; H,6.22; N,11.52.Found: C,68.86; H,6.32; N,11.36.

EXAMPLE 196-(4-Methoxyphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate [1:1]

To a stirred suspension of 0.45 g (0.0187 mole) of sodium hydride in 25ml of anhydrous dimethylformamide under nitrogen atmosphere was added4.5 g (0.015 mole) of6-(4-methoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine over a 30 minperiod. The mixture was stirred for 30 min at room temperature followedby warming at 80°-90° C. for one hr, cooling to room temperature and asolution of 0.019 mole of 3-dimethylaminopropyl chloride in 5 ml ofanhydrous dimethylformamide was added dropwise. The reaction mixture wasstirred overnight at room temperature and poured into 800 ml of water.The suspension was extracted with two 150 ml portions of methylenechloride. The combined extracts were washed with 500 ml of water thenextracted with two 100 ml portions of 3N hydrochloric acid. The solidwhich precipitated from the combined acidic extracts were filtered offand discarded. The filtrate was basified with 3N sodium hydroxide andextracted with three 100 ml portions of methylene chloride. The combinedmethylene chloride extracts were dried over magnesium sulfate andevaporated under reduced pressure. The residual oil had partiallycrystallized and was triturated in methylene chloride and filtered,levaing in a residue of 0.32 g. The filtrate was evaporated underreduced pressure and the residual oil triturated in hot benzene andfiltered, leaving a residue of 0.8 g. The benzene filtrate wasevaporated under reduced pressure and the residual oil was reacted with1.02 g fumaric acid in hot isopropyl alcohol. Upon cooling, an oilseparated from solution. The supernatant liquid was decanted and the oilseeded. After crystallizing partially, the mixture was filtered to give2.5 g solid, m.p. 157°-60° C. An attempted recrystallization fromisopropyl alcohol-isopropyl ether again produced an oil-solid mixture.The mixture was reheated with additional isopropyl alcohol, solubilized,filtered, seeded and cooled. The fumarate salt precipitated and wascollected by filtering to give 2.0 g, m.p. 159°-161° C.

Analysis: Calculated for C₂₈ H₃₀ N₄ O₅ : C,66.92; H,6.02; N,11.15.Found: C,66.90; H,6.08; N,11.08.

EXAMPLE 20 6-(3-Chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

A mixture of 14 g (0.0433 mole) of[2-[(3-amino-2-pyridinyl)amino]phenyl](3-chlorophenyl)-methanone and 0.3g of para toluene sulfonic acid in 500 ml of toluene were heated atreflux overnight using a Dean-Stark trap to collect water. At the end ofthe reflux time, some of the toluene (ca 250 ml) was distilled off andthe hot solution was filtered. Pet. ether (30°-60° C.) was added to thecloud point. The solution was refrigerated overnight and filtered togive, after air drying, 10 g (76%) gold colored crystals. A portion wasrecrystallized from isopropyl alcohol-isopropyl ether, m.p. 160°-160.5°C.

Analysis: Calculated for C₁₈ H₁₂ N₃ Cl: C,70.71; H,3.96; N,13.74. Found:C,70.47; H,3.98; N,13.62.

EXAMPLE 216-(3-Chlorophenyl)N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate [1:1]

To a stirred suspension of 3.4 g (0.07 mole) of sodium hydride (inmineral oil) in 250 ml of anhydrous dimethylformamide was added undernitrogen atmosphere in portions 8.5 g (0.028 mole) of6-(3-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine. The mixture wasstirred for 30 min at room temperature. The temperature was raised to80° C. for 3 hr and thereafter allowed to cool to room temperature. Tothe reaction mixture was added dropwise a solution of 4.9 g (0.031 mole)of 3-dimethylaminopropyl chloride hydrochloride in 30 ml ofdimethylformamide over a 20 minute period. The reaction mixture wasallowed to stir at room temperature overnight under nitrogen atmosphere.Thin layer chromatography indicated some starting material was present.Additional sodium hydride 1.4 g (0.03 mole) was added and after 15 min4.7 g (0.03 mole) of 3-dimethylaminopropyl chloride hydrochloride wasadded followed by stirring for 41/2 hr. Water (20 ml) was added dropwiseand the reaction mixture filtered and concentrated on a rotaryevaporator. The residue was partitioned between diethyl ether and dilutesodium hydroxide. The ether layer was washed with water 3 times andextracted with dilute aqueous hydrochloric acid. The water layer wasbasified with sodium hydroxide pellets and extracted with methylenechloride. The methylene chloride layer was dried and concentrated togive a residue of 7.5 g product. The free base was reacted with fumaricacid and the fumarate salt recrystallized from ethyl acetate-ethanol,m.p. 167.5°-168.5° C.

Analysis: Calculated for C₂₃ H₂₃ N₄ Cl: C,63.96; H,5.47; N,11.05. Found:C,63.95; H,5.39; N,11.00.

EXAMPLE 22 6-(4-Fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

A mixture of 11.5 g (0.037 mole) of[2-[(3-amino-2-pyridinyl)amino]phenyl](4-fluorophenyl)methanone and 0.6g of para toluene sulfonic acid in toluene was refluxed for 24 hr usinga Dean-Stark trap to collect water. At the end of reflux, some of thetoluene (300 ml) was distilled off and the hot solution was filtered.Pet.-ether (30°-60°) was added to cloud point. The solution wasrefrigerated overnight (0° C.) and filtered to give 10.7 g crystals. Aportion of the material was recrystallized from isopropyl alcohol anddried in vacuo overnight at 65° C., m.p. 203°-205° C.

Analysis: Calculated for C₁₈ H₁₂ N₃ F: C,74.73; H,4.18; N,14.52. Found:C,74.61; H,4.17; N,14.54.

EXAMPLE 236-(4-Fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminehydrochloride hemihydrate

To a stirred suspension of 3.6 g (0.075 mole) of sodium hydride (inmineral oil) in 250 ml of anhydrous dimethylformamide was added undernitrogen atmosphere in portions 8.7 g (0.03 mole) of6-(4-fluorophenyl)-11H-pyrido[2,3-][1,4]benzodiazepine. The mixture wasstirred for 30 min at room temperature. The temperature was raised to80° C. for 3.5 hr. and thereafter allowed to cool to 45° C. To thereaction mixture was added dropwise a solution of 5.2 g (0.033 mole) of3-dimethylaminopropyl chloride hydrochloride in 30 ml ofdimethylformamide. After stirring overnight at room temperature, thinlayer chromatography indicated the presence of starting material.Additional sodium hydride, 3.6 g (0.075 mole) was added and after 45 minstirring, the reaction mixture was heated to 50°-60° C. for 1/2 hr. Agreen color developed with formation of gas. The mixture was stirred atroom temperature for 3 hr. A solution of 5.2 g (0.033 mole) of3-dimethylaminopropyl chloride in 30 ml of dimethylformamide was addeddropwise. (About half way through the addition, a green color developedand addition was halted temporarily for about an hour). The reactionmixture was stirred overnight at room temperature. To the mixture wasadded 30 ml of water while cooling. After gas evolution had stopped themixture was filtered and concentrated in a rotary evaporator. Theresidue was partitioned between diethyl ether and water and the etherlayer extracted with dilute aqueous hydrochloric acid solution. Theaqueous layer was filtered after 11/2 hr to remove solid. The filtratewas basified with sodium hydroxide pellets and extracted with methylenechloride. The extract was dried and concentrated. The residue wasdivided into two equal parts and purified by dry column chromatographyon two 20"×11/2" columns of silica gel which had been deactivated by thedevelopment solvent (10% methanol, 1% concentrated ammonium hydroxide,89% methylene chloride). The center portion of the column was cut outand extracted with the development solvent. The combined extracts wereconcentrated under reduced pressure and the residue dissolved in ethylacetate-ethanol mixture and acidified with concentrated hydrochloricacid. The hydrochloric acid salt was recrystallized from ethanol-ethylacetate mixture. The solid obtained by filtration was dried at 99° C.for 48 hr to give the title compound as the monohydrochloridehemihydrate, m.p. 120°-123° C.

Analysis: Calculated for C₄₆ H₅₀ N₈ F₂ Cl₂ O: C,65.78; H,6.00 N,13.34.Found: C,65.58; H,5.77; N,13.47.

EXAMPLE 2411-[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine

To a stirred suspension of 0.56 g (0.023 mole) of sodium hydride in 25ml of anhydrous dimethylformamide was added, portionwise, 5.0 g (0.0184mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reactionmixture was warmed to 80°±2° C. for 1 hr and cooled to room temperature.A solution of 5.55 g (0.020 mole) of N-(3-bromopropyl)phthalimide in 10ml of anhydrous dimethylformamide was added dropwise and after stirringfor 16 hr the reaction mixture was poured into 650 ml of water andstirred for 30 min. The yellow solid was collected by filtration andrecrystallized three times from isopropyl alcohol to give 3.7 g ofproduct, m.p. 170°-172° C.

Analysis: Calculated for C₂₉ H₂₂ N₄ O₂ : C,75.97; H,4.84; N,12.22.Found: C,76.25; H,4.87; N,12.34.

EXAMPLE 25 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,dihydrochloride, hemihydrate

A mixture of 16.2 g (0.035 mole) of6-phenyl-11-[3-(phthalimido)propyl]-11H-pyrido[2,3-b][1,4]benzodiazepineand 2.29 g (0.0387 mole) of hydrazine hydrate, 85% in 175 ml of 190proof ethyl alcohol was refluxed for 2.5 hr and allowed to stand for 72hr. A solution of 10 ml conc. hydrochloride acid in 50 ml of water wasadded to the mixture. The mixture was stirred overnight. The solidprecipitate was collected by filtration and discarded. The filtrate wasevaporated under reduced pressure. The residue, slightly wet, wassuspended in 200 ml of water, the mixture was stirred for 2 hr andfiltered through celite. The filtrate was evaporated under reducedpressure and the residue suspended in 100 ml of 200 proof ethyl alcoholand evaporated under reduced pressure. The latter procedure wasrepeated. The crude, damp residue (42.1 g) was recrystallized fromisopropanol with standing for about 15 hr. The solid, collected byfiltration, was dried at 82° over phosphorus anhydride at 0.1 mm Hg. for3 hr; m.p. 210°-220° C. (decomp.).

Analysis: Calculated for C₄₂ H₄₆ Cl₄ N₈ O: C,61.47; H,5.65; N,13.65.Found: C,61.36; H,5.72; N,13.90.

EXAMPLE 26 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

A portion of the6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,dihydrochloride hemihydrate obtained in Example 25 was dissolved inwater, basified with dilute sodium hydroxide, and extracted with threeportions of methylene chloride. The combined methylene chloride extractswere filtered through a 50-60 g bed of florisil in a sintered glassfunnel. The bed was washed in succession with 1%, 2%, 3% and 5%methanol-methylene chloride mixtures, the filtrates combined andevaporated under reduced pressure to give the free base, the titlecompound. cl EXAMPLE 27

N-[3-[6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepin-11-yl]propyl]methanimidicacid ethyl ester

A solution of 8.8 g (0.021 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in 150 mlof triethylorthoformate was heated at reflux for 41/2 hr and allowed tostand overnight. The mixture was concentrated in vacuo, the residuewashed with pet-ether (30°-60° C.). Chemical ionization mass specindicated the product was a mixture containing the title compound.

EXAMPLE 28N-Methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,dihydrochloride Preparation of Imidate Ester

[Procedure of Crochet, T. A. & Blanton, C. D., Jr. Synthesis 1974 (1)55-56]

6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminedihydrochloride hemihydrate, 25 g (0.06 mole) from Example 25 wasconverted to the free base by partitioning between dilute sodiumhydroxide and methylene chloride, drying and concentrating the methylenechloride layer to dryness, adding dry benzene and again concentrating todrive off the benzene. The resulting free base was dissolved in 300 ml(267 g; 1.8 mole) of freshly distilled triethyl orthoformate withrefluxing for 9 hr. The mixture was concentrated in vacuo, ethanol wasadded and the mixture concentrated again.

Conversion of Amidate to Amine

The 23.4 g (0.061 mole) amidate prepared in the foregoing was dissolvedin 200 ml of ethanol and sodium borohydrate added with stirring at15°-20° C. until thin layer chromatography indicated reaction wasessentially complete as indicated by absence of substantial startingmaterial. Fifty ml of water was added slowly with stirring and coolingcontinued 15 min after the water addition. The mixture was then floodedwith 2 liters of water and extracted with ethyl acetate. The ethylacetate layer was washed with water until neutral wash was obtained andthen saturated with sodium chloride. The resulting ethyl acetate layerwas dried and concentrated. Diethyl ether was added and the mixturechilled. Some insoluble material was filtered off and discarded. Theether layer was concentrated and the product chromatographed on analumina column (neutral, activity-1) eluting with ethylacetate+methanol+traces of triethyl amine. The fractions containingsubstantial product (TLC) were partitioned between ethyl acetate andaqueous sodium hydroxide. Ethereal hydrogen chloride was added to theethyl acetate layer and the crystalline product recrystallized fromacetonitrile-water mixture. Melting point of the product was 139°-141°C.

Analysis: Calculated for C₂₂ H₂₄ N₄ Cl₂ : C,63.62; H,5.82; N,13.49.Found: C,63.81; H,6.15; N,13.60.

EXAMPLE 29N-[3-[6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-yl]propyl]carbamicacid ethyl ester

To a solution of 1.6 g (0.0045 mole) of6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in drymethylene chloride was added 0.53 g (0.0052 mole) of triethylamine. Tothis solution was added dropwise, while cooling, 0.54 g (0.0050 mole) ofethyl chloroformate. The mixture was stirred at room temperature for 2hr. The methylene chloride solution of the product (as indicated bychemical ionization mass spec) was washed with dilute sodiumhydroxide-sodium chloride saturated aqueous solution and dried andconcentrated to dryness. The residue was triturated in isopropyl ether.Yield was 1.5 g of title product.

EXAMPLE 305,6-Dihydro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,dihydrochloride hemihydrate

A solution of 3.0 g (0.0064 mole) ofN,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminein absolute methanol was adjusted to pH 5.6 with methanolic hydrogenchloride solution. To this solution was added at one time, 0.7 g (0.011mole) of NaBH₃ CN and the reaction mixture was refluxed for 20 min. Theethanol was removed in vacuo and the residue was partitioned betweendilute sodium hydroxide and methylene chloride. The methylene chloridelayer was dried over magnesium sulfate and concentrated to leave aresidue which was twice crystallized from 2-propanol and isopropylether. A yellow solid, 1.6 g (57%) was obtained which loses itscrystalline structure on heating starting at 156°-160° C. withdecomposition at 180°-195° C.

Analysis: Calculated for C₄₆ H₅₈ N₈ OCl₄ : C,62.73; H,6.64; N,12.72.Found: C,62.40; H,6.90 N,12.61.

EXAMPLES 31a TO 31r

Following the procedure of Example 6, the following methanone compounds:

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-ethylphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-isopropylphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-bromophenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-fluorophenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-ethoxyphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-nitrophenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-trifluoromethylphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-methylphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-ethylphenyl)methanone,

[2-(3-amino-2-pyridinyl)amino]phenyl]-(3-methoxyphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-ethoxyphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-nitrophenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-trifluoromethylphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-methylphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-ethylphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-methoxyphenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl]-2,4-dichlorophenyl)methanone, and

[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3,4,5-trimethoxyphenyl)methanone,

are cyclized to the following pyridobenzodiazepines:

(a) 6-(4-ethylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(b) 6-(4-isopropylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(c) 6-(4-bromophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(d) 6-(4-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(e) 6-(4-ethoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(f) 6-(4-nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(g) 6-(4-trifluoromethylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(h) 6-(3methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(i) 6-(3-ethylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(j) 6-(3-methoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(k) 6-(3-ethoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(l) 6-(2-nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(m) 6-(3-trifluoromethylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(n) 6-(2-methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(o) 6-(2-ethylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(p) 6-(2-methoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(q) 6-(2,4-dichlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, and

(r) 6-(3,4,5-trimethoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine.

EXAMPLES 32a TO 32o

Following the procedure of Example 3, the following methanone compounds:

[2-[(3-amino-2-pyridinyl)amino]-5-chlorophenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-6-chlorophenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-bromophenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-fluorophenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-trifluoromethylphenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-methylphenyl](phenyl)methanone,

[2-[(3-amino2-pyridinyl)amino]-5-methylphenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-6-methylphenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-ethylphenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-methoxyphenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-ethoxyphenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-4-nitrophenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-5-nitrophenyl](phenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]-3-methylphenyl](phenyl)methanone, and

[2-[(3-amino-2-pyridinyl)amino-3-chlorophenyl](phenyl)methanone,

are cyclized to the following benzodiazepines:

(a) 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(b) 7-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(c) 9-bromo-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(d) 9-fluoro-6-phenyl-11H-pyrido[2,3-b]1,4 benzodiazepine,

(e) 6-phenyl-9-trifluoromethyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(f) 9-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(g) 8-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(h) 7-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(i) 9-ethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(j) 9-methoxy-6-phenyl-11H-pyrido[2,3-b][1,4]-benzodiazepine,

(k) 9-ethoxy-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(l) 9-nitro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(m) 8nitro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(n) 10-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, and

(o) 10-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine.

EXAMPLES 33a TO 33r

Utilizing the procedure of Example 15 but substituting equal molaramounts of each of the compounds prepared in Example 31, the following6-phenyl-substituted pyridobenzodiazepines are prepared:

(a)6-(4-ethylphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(b)N,N-dimethyl-6-[4-(1-methylethyl)phenyl]-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(c)6-(4-bromophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(d)6-(4fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(e)6-(4-ethoxyphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(f)N,N-dimethyl-6-(4-nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(g)N,N-dimethyl-6-[4-(trifluoromethyl)phenyl]-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(h)N,N-dimethyl-6-(3-methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(i)6-(3-ethylphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(j)6-(3-methoxyphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(k)6-(3-ethoxyphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(l)N,N-dimethyl-6-(2-nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(m)N,N-dimethyl-6-[4-(trifluoromethyl)phenyl]-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(n)N,N-dimethyl-6-(2-methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(o)6-(2-ethylphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(p)6-(2-methoxyphenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(q)6-(2,4-dichlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,and

(r)N,N-dimethyl-6-(3,4,5-trimethoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

EXAMPLES 34a TO 34o

Utilizing the procedure of Example 13 but substituting equal molaramounts of the compounds prepared in Example 32 for9-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, the followingpyridobenzodiazepines are prepared:

(a)8-chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(b)7-chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(c)9-bromo-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(d)9-fluoro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(e)N,N-dimethyl-6-phenyl-9-(trifluoromethyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(f)N,N,9-trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(g)N,N,8-trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(h)N,N7-trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(i)9-ethyl-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(j)9-methoxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4benzodiazepine-11-propanamine,

(k)9-ethoxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(l)N,N-dimethyl-9-nitro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(m)N,N-dimethyl-8-nitro-6-phenyl-1H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(n)N,N-10,trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,and

(o)10-chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

EXAMPLES 35a TO 35c

Following the procedure of Example 1 and substituting equal molaramounts of the following for 3-amino-2-chloropyridine:

4-amino-3-chloropyridine,

3-amino-4-chloropyridine, and

2-amino-3-chloropyridine,

there are obtained:

(a) 6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine,

(b) 10-phenyl-5H-pyrido[4,3-b][1,4]benzodiazepine, and

(c) 10phenyl-5H-pyrido[3,2-b][1,4]benzodiazepine.

EXAMPLES 36a TO 36c

Following the procedure of Example 3, the following:

[2-[(4amino-3-pyridinyl)amino]phenylmethanone,

[2-[(3amino-4-pyridinyl)amino]phenylmethanone, and

[2-[(2-amino-3-pyridinyl)amino]phenylmethanone,

are converted to:

(a) 6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine,

(b) 10-phenyl-5H-pyrido[4,3-b][1,4]benzodiazepine, and

(c) 10-phenyl-5H-pyrido[3,2-b][1,4]benzodiazepine.

EXAMPLES 37a TO 37c

Following the procedure of Example 9 and substituting equal molaramounts of the following for6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine:

6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine,

10-phenyl-5H-pyrido[4,3-b][1,4]benzodiazepine, and

10-phenyl-5H-pyrido[3,2-b][1,4]benzodiazepine,

there are obtained:

(a)N,N-dimethyl-6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine-11-propanaminefumarate,

(b)N,N-dimethyl-10-phenyl-5H-pyrido[4,3-b][1,4]benzodiazepine-5-propanaminefumarate, and

(c)N,N-dimethyl-10-phenyl-5H-pyrido[3,2-b][1,4]benzodiazepine-5-propanaminefumarate.

EXAMPLE 385,6-Dihydro-6-phenyl-N-methyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

To a solution of 1.4 g (0.0035 mole) ofN-[3-[6-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-yl]propyl]carbamicacid ethyl ester (from Example 29) in tetrahydrofuran under nitrogen gaswas added 0.4 g (0.0105 mole) of lithium aluminum hydride and slightexothermic reaction occurred. The mixture was cooled to preventoverheating. The mixture was stirred at reflux temperature for 16 hr.Thin layer chromatography indicated only partial conversion hadoccurred. An additional 0.4 g (0.0105 mole) of lithium aluminum hydridewas added and the mixture refluxed overnight. Thin-layer chromatographyindicated the product was predominantly the title compound.

EXAMPLE 39 6-(2-Thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedure of Example 20,[2-[(3-amino-2-pyridinyl)amino]phenyl](2-thienyl)methanone is heatedwith para toluene sulfonic acid catalyst in organic solvent whileremoving water in a Dean-Stark trap to give the title compound.

EXAMPLE 40 6-(3-Thienyl)-11H-pyrido[2,3-b][1,4-benzodiazepine

Following the procedure of Example 20,[2-[(3-amino-2-pyridinyl)amino]phenyl](3-thienyl)methanone is heatedwith para toluene sulfonic acid catalyst in organic solvent whileremoving water in a Dean-Stark trap to give the title compound.

EXAMPLE 41 6-(2-Pyridinyl)-11H-pyrido[2,3-b][1,4]-benzodiazepine

Following the procedure of Example 3,[2-[(3-amino-2-pyridinyl)amino]phenyl](2-pyridinyl)methanone is cyclizedto the title compound.

EXAMPLE 42 6-(3-Pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedure of Example 3,[2-[(3-amino-2-pyridinyl)amino]phenyl](3-pyridinyl)methanone is cyclizedto the title compound.

EXAMPLE 43 6-(4-Pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine

Following the procedure of Example 3,[2-[(3-amino-2-pyridinyl)amino]phenyl](4-pyridinyl)methanone is cyclizedto the title compound.

EXAMPLE 44N,N-Dimethyl-6-(2-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

Following the procedure of Example 23,6-(2-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted withsodium hydride followed by reaction with 3-dimethylaminopropyl chlorideto give the title compound.

EXAMPLE 45N,N-Dimethyl-6-(3-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

Following the procedure of Example 23,6-(3-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted withsodium hydride followed by reaction with 3-dimethylaminopropyl chlorideto give the title compound.

EXAMPLE 46N,N-Dimethyl-6-(2-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

Following the procedure of Example 23,6-(2-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted withsodium hydride followed by reaction with 3-dimethylaminopropyl chlorideto give the title compound.

EXAMPLE 47N,N-Dimethyl-6-(3-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

Following the procedure of Example 23,6-(3-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted withsodium hydride followed by reaction with 3-dimethylaminopropyl chlorideto give the title compound.

EXAMPLE 48N,N-Dimethyl-6-(4-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

Following the procedure of Example 23,6-(4-pyridinyl)-11H-pyrido[2,3-b][1,4]-benzodiazepine is reacted withsodium hydride followed by reaction with 3-dimethylaminopropyl chloride.

EXAMPLES 49a TO 49g

Following the procedure of Example 6, the following methanone compoundsof Intermediate 15:

[2-[(3-amino-4-methyl-2-pyridinyl)amino]phenyl]phenylmethanone,

[2-[(3-amino-5-methyl-2-pyridinyl)amino]phenyl]phenylmethanone,

[2-[(3-amino-6-methyl-2-pyridinyl)amino]phenyl]phenylmethanone,

[2-[(3-amino-5,6-dimethyl-2-pyridinyl)amino]phenyl]phenylmethanone,

[2-[(3-amino-6-methoxy-2-pyridinyl)amino]phenyl]phenylmethanone,

[2-[(3-amino-2-methyl-4-pyridinyl)amino]phenyl]phenylmethanone, and

[2-[(3-amino-5-methoxy-2-pyridinyl)amino]phenyl]phenylmethanone,

are converted to the following pyridobenzodiazepines:

(a) 4-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(b) 3-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(c) 2-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(d) 2,3-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(e) 2-methoxy-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(f) 1-methyl-10-phenyl-5H-pyrido[4,3-b][1,4]benzodiazepine, and

(g) 3-methoxy-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine.

EXAMPLES 50a TO 50g

Following the procedure of Example 23, the pyridobenzodiazepinesprepared in Example 49 are reacted with sodium hydride and3-dimethylaminopropyl chloride to give the following:

(a)N,N,4-trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(b)N,N,3-trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(c)N,N,2-trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(d)N,N,2,3-tetramethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(e)2-methoxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,

(f)N,N,1-trimethyl-10-phenyl-5H-pyrido[4,3-b][1,4]benzodiazepine-5-propanamine,and

(g)3-methoxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine.

EXAMPLES 51a TO 51c

Following the procedure of Example 22 but substituting the following for[2-[(3-amino-2-pyridinyl)amino]phenyl](4-fluorophenyl)methanone:

[2-[(3-amino-2-pyridinyl)amino]phenyl](2-fluorophenyl)methanone,

[2-[(3-amino-2-pyridinyl)amino]phenyl](2-chlorophenyl)methanone, and

[2-[(3-amino-2-pyridinyl)amino]phenyl](2-bromophenyl)methanone,

there are obtained:

(a) 6-(2-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

(b) 6-(2-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, and

(c) 6-(2-bromophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine.

EXAMPLES 52a TO 52c

Following the procedure of Example 23, substituting the followingpyrido[1,4]benzodiazepines for6-(4-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine:

6-(2-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

6-(2-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

6-(2-bromophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

there are obtained:

(a)6-(2-fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,m.p. 92°-94° C.; recrystalizing solvent isopropyl alcohol-isopropylether,

(b)6-(2-chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3][1,4]benzodiazepine-11-propanamine,m.p. 104°-105° C.; recrystallizing solvent: isopropyl ether, and

(c)6-(2-bromophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine,m.p. 96°-98° C.; recrystallizing solvent: isopropyl ether.

EXAMPLES 53a AND 53b

Following the procedure of Example 9, the following are substituted for3-dimethylaminopropyl chloride:

3-dimethylamino-2-methylpropyl chloride, and

4-dimethylaminobutyl chloride,

there are obtained:

(a)N,N,β-trimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminefumarate, and

(b)N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-butanaminefumarate.

EXAMPLES 54a AND 54b

When in the procedure of Example 11 the following are substituted for4-(3-chlorophopyl)morpholine hydrochloride:

1-(3-chloropropyl)pyrrolidine hydrochloride, and

1-(3-chloropropyl)-4-methylpiperazine hydrochloride,

there are obtained:

6-phenyl-11-[3-(1-pyrrolidinyl)propyl]-11H-pyrido[2,3-b][1,4]-benzodiazepine,and

6-phenyl-11-[3-(4-methyl-1-piperazinyl)propyl]-11H-pyrido[2,3-b][1,4]benzodiazepine.

EXAMPLES 55a TO 55c

When in the procedure of Example 9 the following are substituted for6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine:

8-methyl-6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine,

6-(4-chlorophenyl)-11H-pyrido[3,4-b][1,4]benzodiazepine, and

3-methoxy-6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine,

there are obtained:

(a)N,N,8-trimethyl-6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine-11-propanamine,and

(b)6-(4-chlorophenyl)-N,N-dimethyl-11H-pyrido[3,4-b][1,4]benzodiazepine-11-propanamine,and

(c)3-methoxy-N,N-dimethyl-6-phenyl-11H-pyrido[3,4-b][1,4]benzodiazepine-11-propanamine.

EXAMPLES 56a TO 56d

When in the procedure of Example 17 the following are substituted for8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine:

6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

8-chloro-6-(2-nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

8chloro-6-(2-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, and

8chloro-6-(2-bromophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

there are obtained:

(a) 11-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine,

(b)8-chloro-11-methyl-6-(2nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,m.p. 165°-166° C., recrystallizing solvent: ethyl alcohol,

(c)8-chloro-6-(2-chlorophenyl)-11-methyl-11H-pyrido[2,3-b][1,4]benzodiazepine,m.p. 150°-152° C., recrystallizing solvent: isopropyl alcohol-isopropylether, and

(d)6-(2-bromophenyl)-3-chloro-11-methyl-11H-pyrido[2,3-b][1,4]benzodiazepine,m.p. 121°-123° C., recrystallizing solvent: isopropyl ether.

EXAMPLE 57N-Methyl-N-[3-(3-(11H-pyrido[2,3-b][1,4]benzodiazepine-11-yl)propyl]carbamicacid methyl ester

The title compound is prepared by reacting6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine and(3-chloropropyl)methylcarbamic acid methyl ester.

EXAMPLE 589-Hydroxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

The title compound is prepared by reacting11-[3-(dimethylamino)propyl]-9-methoxy-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepinewith hydrogen iodide and glacial acetic acid.

EXAMPLE 593-Hydroxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine

The title compound is prepared by reacting3-methoxy-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanaminewith hydrogen iodide and glacial acetic acid.

                                      TABLE 2                                     __________________________________________________________________________    Example                                                                            R           Ar        Y     Z    n Salt                                  __________________________________________________________________________     ##STR25##                                                                    1    H           C.sub.6 H.sub.5                                                                         H     H    0 --                                    2    H           C.sub.6 H.sub.5                                                                         H     8-Cl 0 --                                    3    H           C.sub.6 H.sub.5                                                                         H     9-Cl 0 --                                    4    H           2-ClC.sub.6 H.sub.4                                                                     H     8-Cl 1 --                                    5    H           4-ClC.sub.6 H.sub.4                                                                     H     H    0 --                                    6    H           4-CH.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    7    H           4-OCH.sub.3C.sub.6 H.sub.4                                                              H     H    0 --                                    8    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     8-Cl 0 oxalate                               9    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    0 fumarate                              10   (CH.sub.2).sub.2N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    0 fumarate                              11   (CH.sub.2).sub.34-                                                                        C.sub.6 H.sub.5                                                                         H     H    0 fumarate                                   morpholinyl                                                              12   (CH.sub.2).sub.3N(C.sub.2 H.sub.5).sub.2                                                  C.sub.6 H.sub.5                                                                         H     H    0 oxalate                               13   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-Cl 0 fumarate                              14   (CH.sub.2).sub.31-                                                                        C.sub.6 H.sub.5                                                                         H     H    0 fumarate                                   piperidinyl                                                              15   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-ClC.sub.6 H.sub.4                                                                     H     H    0 fumarate                              16   (CH.sub.2).sub.2N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     8-Cl 0 oxalate                               17   CH.sub.3    C.sub.6 H.sub.5                                                                         H     8-Cl 0 --                                    18   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-CH.sub.3C.sub. 6 H.sub.4                                                              H     H    0 fumarate                              19   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-OCH.sub.3C.sub.6 H.sub.4                                                              H     H    0 fumarate                              20   H           3-ClC.sub.6 H.sub.4                                                                     H     H    0 --                                    21   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-ClC.sub.6 H.sub.4                                                                     H     H    0 fumarate                              22   H           4-FC.sub.6 H.sub.4                                                                      H     H    0 --                                    23   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-FC.sub.6 H.sub.4                                                                      H     H    0 HCl,                                                                          1/2 H.sub.2 O                         24   (CH.sub.2).sub.31-                                                                        C.sub.6 H.sub.5                                                                         H     H    0 --                                         phthalimido                                                              25   (CH.sub.2).sub.3NH.sub.2                                                                  C.sub.6 H.sub.5                                                                         H     H    0 2 HCl,                                                                        2 H.sub.2 O                           26   (CH.sub.2).sub.3NH.sub.2                                                                  C.sub.6 H.sub.5                                                                         H     H    0 --                                    27   (CH.sub.2).sub.3NCH                                                                       C.sub.6 H.sub.5                                                                         H     H    0 --                                         OC.sub.2 H.sub.5                                                         28   (CH.sub.2).sub.3 NHCH.sub.3                                                               C.sub.6 H.sub.5                                                                         H     H    0 2 HCl                                 29   (CH.sub.2).sub.3NHC(O)                                                                    C.sub.6 H.sub.5                                                                         H     H    0 --                                         OC.sub.2 H.sub.5                                                         30   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    1 2 HCl,                                                                        0.5 H.sub.2 O                         31 a H           4-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                        H     H    0 --                                    b    H           4-i-C.sub.3 H.sub.7C.sub.6 H.sub.4                                                      H     H    0 --                                    c    H           4-BrC.sub.6 H.sub.4                                                                     H     H    0 --                                    d    H           4-FC.sub.6 H.sub.4                                                                      H     H    0 --                                    e    H           4-OC.sub.2 H.sub.5C.sub.6 H.sub.4                                                       H     H    0 --                                    f    H           4-NO.sub.2C.sub.6 H.sub.4                                                               H     H    0 --                                    g    H           4-CF.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    h    H           4-CH.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    i    H           3-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                        H     H    0 --                                    j    H           3-OCH.sub.3C.sub.6 H.sub.4                                                              H     H    0 --                                    k    H           3-OC.sub.2 H.sub.5C.sub.6 H.sub.4                                                       H     H    0 --                                    l    H           2-NO.sub.2C.sub.6 H.sub.4                                                               H     H    0 --                                    m    H           3-CF.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    n    H           2-CH.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    o    H           2-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                        H     H    0 --                                    p    H           2-OCH.sub.3C.sub.6 H.sub.4                                                              H     H    0 --                                    q    H           2,4(Cl).sub.2C.sub.6 H.sub.3                                                            H     H    0 --                                    r    H           3,4,5-(OCH.sub.3).sub.3                                                                 H     H    0 --                                                     C.sub.6 H.sub.2                                              32 a H           C.sub.6 H.sub.5                                                                         H     8-Cl 0 --                                    b    H           C.sub.6 H.sub.5                                                                         H     7-Cl 0 --                                    c    H           C.sub.6 H.sub.5                                                                         H     9-Br 0 --                                    d    H           C.sub.6 H.sub.5                                                                         H     9-F  0 --                                    e    H           C.sub.6 H.sub.5                                                                         H     9-CF.sub.3                                                                         0 --                                    f    H           C.sub.6 H.sub.5                                                                         H     9-CH.sub.3                                                                         0 --                                    g    H           C.sub.6 H.sub.5                                                                         H     8-CH.sub.3                                                                         0 --                                    h    H           C.sub.6 H.sub.5                                                                         H     7-CH.sub.3                                                                         0 --                                    i    H           C.sub.6 H.sub.5                                                                         H     9-C.sub.2 H.sub.5                                                                  0 --                                    j    H           C.sub.6 H.sub.5                                                                         H     9-OCH.sub.3                                                                        0 --                                    k    H           C.sub.6 H.sub.5                                                                         H     9-OC.sub.2 H.sub.5                                                                 0 --                                    l    H           C.sub.6 H.sub.5                                                                         H     9-NO.sub.2                                                                         0 --                                    m    H           C.sub.6 H.sub.5                                                                         H     8-NO.sub.2                                                                         0 --                                    n    H           C.sub.6 H.sub.5                                                                         H     10-CH.sub.3                                                                        0 --                                    o    H           C.sub.6 H.sub.5                                                                         H     10-Cl                                                                              0 --                                    33 a (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                        H     H    0 --                                    b    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-i-C.sub.3 H.sub.7C.sub.6 H.sub.4                                                      H     H    0 --                                    c    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-BrC.sub.6 H.sub.4                                                                     H     H    0 --                                    d    (CH.sub. 2).sub.3N(CH.sub.3).sub.2                                                        4-FC.sub.6 H.sub.4                                                                      H     H    0 --                                    e    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-OC.sub.2 H.sub.5C.sub.6 H.sub.4                                                       H     H    0 --                                    f    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-NO.sub.2C.sub.6 H.sub.4                                                               H     H    0 --                                    g    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-CF.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    h    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-CH.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    i    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                        H     H    0 --                                    j    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-OCH.sub.3C.sub.6 H.sub.4                                                              H     H    0 --                                    k    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-OC.sub.2 H.sub.5C.sub.6 H.sub.4                                                       H     H    0 --                                    l    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-NO.sub.2C.sub.6 H.sub.4                                                               H     H    0 --                                    m    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-CF.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    n    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-CH.sub.3C.sub.6 H.sub.4                                                               H     H    0 --                                    o    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-C.sub.2 H.sub.5C.sub.6 H.sub.4                                                        H     H    0 --                                    p    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-OCH.sub.3C.sub.6 H.sub.4                                                              H     H    0 --                                    q    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2,4-(Cl).sub.2C.sub.6 H.sub.3                                                           H     H    0 --                                    r    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3,4,5-(OCH.sub.3).sub.3                                                                 H     H    0 --                                                     C.sub.6 H.sub.2                                              34 a (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     8-Cl 0 --                                    b    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     7-Cl 0 --                                    c    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-Br 0 --                                    d    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-F  0 --                                    e    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-CF.sub.3                                                                         0 --                                    f    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-CH.sub.3                                                                         0 --                                    g    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     8-CH.sub.3                                                                         0 --                                    h    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     7-CH.sub.3                                                                         0 --                                    i    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-C.sub.2 H.sub.5                                                                  0 --                                    j    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-OCH.sub.3                                                                        0 --                                    k    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-OC.sub.2 H.sub.5                                                                 0 --                                    l    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-NO.sub.2                                                                         0 --                                    m    (CH.sub.2).sub.3N(CH.sub.3).sub. 2                                                        C.sub.6 H.sub.5                                                                         H     8-NO.sub.2                                                                         0 --                                    n    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     10-CH.sub.3                                                                        0 --                                    o    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     10-Cl                                                                              0 --                                    38   (CH.sub.2).sub.3 NHCH.sub.3                                                               C.sub.6 H.sub.5                                                                         H     H    1 --                                    39   H           2-thienyl H     H    0 --                                    40   H           3-thienyl H     H    0 --                                    41   H           2-pyridinyl                                                                             H     H    0 --                                    42   H           3-pyridinyl                                                                             H     H    0 --                                    43   H           4-pyridinyl                                                                             H     H    0 --                                    44   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-thienyl H     H    0 --                                    45   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-thienyl H     H    0 --                                    46   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-pyridinyl                                                                             H     H    0 --                                    47   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         3-pyridinyl                                                                             H     H    0 --                                    48   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         4-pyridinyl                                                                             H     H    0 --                                    49 a H           C.sub.6 H.sub.5                                                                         4-CH.sub.3                                                                          H    0 --                                    b    H           C.sub.6 H.sub.5                                                                         3-CH.sub.3                                                                          H    0 --                                    c    H           C.sub.6 H.sub.5                                                                         2-CH.sub.3                                                                          H    0 --                                    d    H           C.sub.6 H.sub.5                                                                         2,3-(CH.sub.3).sub.2                                                                H                                            e    H           C.sub.6 H.sub.5                                                                         2-OCH.sub.3                                                                         H    0 --                                    g    H           C.sub.6 H.sub.5                                                                         3-OCH.sub.3                                                                         H    0 --                                    50 a (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         4-CH.sub.3                                                                          H    0 --                                    b    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         3-CH.sub.3                                                                          H    0 --                                    c    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         2-CH.sub.3                                                                          H    0 --                                    d    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         2,3-(CH.sub.3).sub.2                                                                H    0 --                                    e    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         2-OCH.sub.3                                                                         H    0 --                                    g    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         3-OCH.sub.3                                                                         H    0 --                                    51 a H           2-FC.sub.6 H.sub.4                                                                      H     H    0 --                                    b    H           2-ClC.sub.6 H.sub.4                                                                     H     H    0 --                                    c    H           2-BrC.sub.6 H.sub.4                                                                     H     H    0 --                                    52 a (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-FC.sub.6 H.sub.4                                                                      H     H    0 --                                    b    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-ClC.sub.6 H.sub.4                                                                     H     H    0 --                                    c    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         2-BrC.sub.6 H.sub.4                                                                     H     H    0 --                                    53 a CH.sub.2 CH(CH.sub.3)CH.sub.2                                                             C.sub.6 H.sub.5                                                                         H     H    0 fumarate                                   N(CH.sub.3).sub.2                                                        b    (CH.sub.2).sub.4N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    0 fumarate                              54 a (CH.sub.2).sub.31-                                                                        C.sub.6 H.sub.5                                                                         H     H    0 --                                         pyrrolidinyl                                                             b    (CH.sub.2).sub.34-                                                                        C.sub.6 H.sub.5                                                                         H     H    0 --                                         methylpiperazin-                                                              1-yl                                                                     56 a CH.sub.3    C.sub.6 H.sub.5                                                                         H     H    0 --                                    b    CH.sub.3    2-NO.sub.2C.sub.6 H.sub.4                                                               H     8-Cl 0 --                                    c    CH.sub.3    2-ClC.sub.6 H.sub.4                                                                     H     8-Cl 0 --                                    d    CH.sub.3    2-BrC.sub.6 H.sub.4                                                                     H     8-Cl 0 --                                    57   (CH.sub.2).sub.3N(CH.sub.3)                                                               C.sub.6 H.sub.5                                                                         H     H    0 --                                         C(O)OCH.sub.3                                                            58   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     9-OH 0 --                                    59   (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         3-OH  H    0 --                                     ##STR26##                                                                     35 a                                                                              H           C.sub.6 H.sub.5                                                                         H     H    0 --                                    36 a H           C.sub.6 H.sub.5                                                                         H     H    0 --                                    37 a (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    0 fumarate                              55 a (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     8-CH.sub.3                                                                         0 --                                    b    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         3-OCH.sub.3                                                                         H    0 --                                    c    (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    0 --                                     ##STR27##                                                                    35 b H           C.sub.6 H.sub.5                                                                         H     H    0 --                                    36 b H           C.sub.6 H.sub.5                                                                         H     H    0 --                                    37 b (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    0 fumarate                              49 f H           C.sub.6 H.sub.5                                                                         1-CH.sub.3                                                                          H    0 --                                    50 f (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         1-CH.sub.3                                                                          H    0 --                                     ##STR28##                                                                    35 c  H          C.sub.6 H.sub.5                                                                         H     H    0 --                                    36 c H           C.sub.6 H.sub.5                                                                         H     H    0 --                                    37 c (CH.sub.2).sub.3N(CH.sub.3).sub.2                                                         C.sub.6 H.sub.5                                                                         H     H    0 fumarate                              __________________________________________________________________________

FORMULATION AND ADMINISTRATION

Effective quantities of the foregoing pharmacologically active compoundsof Formula Ip or Formula II may be administered to humans fortherapeutic purposes according to usual modes of administration and inusual forms, such as orally in solutions, emulsions, suspensions, pills,tablets and capsules, in pharmaceutically acceptable carriers andparenterally in the form of sterile solutions.

Exemplary of solid carriers for oral administration are such as lactose,magnesium, stearate, terra alba, sucrose, talc, stearic acid, gelatin,agar, pectin or acacia.

Exemplary of liquid carriers for oral administration are vegetable oilsand water.

For intramuscular administration the carrier or excipient may be asterile, parenterally acceptable liquid; e.g., water or a parenterallyacceptable oil; e.g., arachis oil contained in ampules. Although verysmall quantities of the active materials of the present invention areeffective when minor therapy is involved or in cases of administrationto subjects having a relatively low body weight, unit dosages areusually from five milligrams or above and preferably 10, 25, 50, or 100milligrams or even higher, preferably administered three or four timesper day, depending, of course, upon the emergency of the situation, thecompound used, and the particular result desired. Twenty-five to 200milligrams appears optimum per unit dose or usual broader ranges appearto be about 10 to 500 milligrams per unit dose. Daily dosages usuallyrequired should range from about 0.3 to about 20 mg/kg/day, preferably0.3 to 10 mg/kg for the more active compounds. The active ingredients ofthe invention may be combined with other compatible pharmacologicallyactive agents. It is only necessary that the active ingredientconstitute an effective amount; i.e., such that a suitable effectivedosage will be obtained consistent with the dosage form employed.Obviously, several unit dosage forms may be administered at about thesame time. The exact individual dosages as well as daily dosages will,of course, be determined according to standard medical principles underthe direction of a physician.

The following formulations are representative for the pharmacologicallyactive compounds of this invention.

FORMULATIONS

1. Capsules

Capsules of 10 mg and 50 mg of active ingredient per capsule areprepared. With the higher amounts of active ingredient, reduction may bemade in the amount of lactose.

    ______________________________________                                                          10 mg.     50 mg.                                           Typical blend for encapsulation                                                                 Per Capsule                                                                              Per Capsule                                      ______________________________________                                        Active ingredient, as salt                                                                       10         50                                              Lactose           259        219                                              Starch            126        126                                              Magnesium stearate                                                                               4          4                                               Total             399        399                                              ______________________________________                                    

Additional capsule formulations preferably contain a higher dosage ofactive ingredient and are as follows:

    ______________________________________                                                     100         250      500                                                      mg. per     mg. per  mg. per                                     Ingredients  Capsule     Capsule  Capsule                                     ______________________________________                                        Active ingredient,                                                                         100         250      500                                         as salt                                                                       Lactose      214         163      95                                          Starch        87          81      47                                          Magnesium stearate                                                                          4           6        8                                          Total        399         500      650                                         ______________________________________                                    

In each case, uniformly blend the selected active ingredient withlactose, starch, and magnesium stearate and encapsulate the blend.

2. Tablets

A typical formulation for a tablet containing 5.0 mg of activeingredient per tablet follows. The formulation may be used for otherstrengths of active ingredient by adjustment of weight of dicalciumphosphate.

    ______________________________________                                                        Per Tablet, mg.                                               ______________________________________                                        1. Active ingredient                                                                            10.0                                                        2. Corn starch    15.0                                                        3. Corn starch (paste)                                                                          12.0                                                        4. Lactose        35.0                                                        5. Dicalcium phosphate                                                                          132.0                                                       6. Calcium stearate                                                                              2.0                                                        Total             202.0                                                       ______________________________________                                    

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water.Granulate the blend with starch paste and pass the wet mass through an 8mesh screen. The wet granulation is dried and sized through a 12 meshscreen. The dried granules are blended with the calcium stearate andcompressed.

3. Injectable--2% sterile solution

    ______________________________________                                                              Per cc                                                  ______________________________________                                        Active ingredient       mg.    20                                             Preservative, e.g.,            0.5                                            chlorobutanol, w/vol. percent                                                 Water for injection q.s.                                                      ______________________________________                                    

Prepare solution, clarify by filtration, fill into vials, seal andautoclave.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, compositions and methods ofthe present invention without departing from the spirit and scopethereof, and it is therefore understood that the invention is to belimited only by the scope of the appended claims.

What is claimed is:
 1. A compound selected from the group having theformula: ##STR29## wherein; R is selected from the group consisting ofhydrogen, loweralkyl, --alk¹ --halo, --alk¹ --NR¹ R² or --alk¹--N═CH--OCH₂ H₅ ;R¹ and R² are selected from the group consisting ofhydrogen, loweralkyl, or --C(O)O-loweralkyl; B is selected fromcarbonyl, thioxomethyl, ##STR30## Ar is selected from the groupconsisting of 2, 3 and 4 pyridinyl, 2 or 3 thienyl, phenyl or phenylsubstituted by 1 to 3 radicals selected from halo, loweralkyl,loweralkoxy, trifluoromethyl or nitro and may be the same or different;alk¹ is a straight or branched hydrocarbon chain containing 1-8 carbonatoms; Z is selected from the group consisting of hydrogen, halogen,loweralkyl, loweralkoxy, hydroxy or nitro; Y is selected from the groupconsisting of hydrogen or 1-2 radicals selected from loweralkyl,loweralkoxy or hydroxy and may be the same or different; and apharmaceutically acceptable acid addition salt thereof.
 2. The compoundof claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl]phenylmethanone.
 3. The compoundof claim 1 which is[2-[(3-amino-2-pyridinyl)amino]-4-chlorophenyl]phenylmethanone.
 4. Thecompound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl](4-methylphenyl)methanone.
 5. Thecompound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]-5-chlorophenyl](2-chlorophenyl)methanone.6. The compound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]-3-chlorophenyl]phenylmethanone.
 7. Thecompound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]-4-fluorophenyl]phenylmethanone.
 8. Thecompound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl](3-chlorophenyl)methanone.
 9. Thecompound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl](4-fluorophenyl)methanone.
 10. Thecompound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-trifluoromethylphenyl)methanone.11. The compound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-fluorophenyl)methanone. 12.The compound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-fluorophenyl)methanone. 13.The compound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-chlorophenyl)methanone. 14.The compound of claim 1 which is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-bromophenyl)methanone.
 15. Amethod of treating depression in a living animal which comprisesadministering thereto an effective amount for treating depression of acompound having the formula ##STR31## wherein; R is selected from thegroup consisting of hydrogen, loweralkyl or --alk¹ --NR¹ R² ;R¹ and R²are selected from the group consisting of hydrogen or loweralkyl; alk¹is a straight or branched hydrocarbon chain containing 1-8 carbon atoms;B is selected from carbonyl or thioxomethyl; Ar is selected from thegroup consisting of 2, 3 and 4-pyridinyl, 2 or 3-thienyl, phenyl orphenyl substituted by 1 to 3 radicals selected from halo, loweralkyl,loweralkoxy, trifluoromethyl or nitro and may be the same or different;Z is selected from the group consisting of hydrogen, halogen,loweralkyl, loweralkoxy, hydroxy, or nitro; Y is selected from the groupconsisting of hydrogen or 1-2 radicals selected from loweralkyl, hydroxyor loweralkoxy and may be the same or different, and a pharmaceuticallyacceptable acid addition salt thereof.
 16. The method of claim 15wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]phenylmethanone.
 17. The method ofclaim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-4-chlorophenyl]phenylmethanone.
 18. Themethod of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](4-methylphenyl)methanone.
 19. Themethod of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-5-chlorophenyl](2-chlorophenyl]methanone.20. The method of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-3-chlorophenyl]phenylmethanone.
 21. Themethod of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-4-fluorophenyl]phenylmethanone.
 22. Themethod of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-chlorophenyl)methanone. 23.The method of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-fluorophenyl)methanone. 24.The method of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]-[3-trifluoromethylphenyl)methanone.25. The method of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-fluorophenyl)methanone. 26.The method of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-fluorophenyl)methanone. 27.The method of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-chlorophenyl)methanone. 28.The compound of claim 15 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-bromophenyl)methanone.
 29. Apharmaceutical composition for treating depression in unit dosage formcomprising (a) an effective amount for treating depression of a compoundhaving the formula: ##STR32## wherein; R is selected from the groupconsisting of hydrogen, loweralkyl, or --alk¹ --NR¹ r² ;R¹ and R² areselected from the group consisting of hydrogen or loweralkyl; alk¹ is astraight or branched hydrocarbon chain containing 1-8 carbon atoms; B isselected from carbonyl or thioxomethyl; Ar is selected from the groupconsisting of 2, 3 and 4-pyridinyl, 2-3-thienyl, phenyl or phenylsubstituted by 1 to 3 radicals selected from halo, loweralkyl,loweralkoxy, trifluoromethyl or nitro and may be the same or different;Z is selected from the group consisting of hydrogen, halogen,loweralkyl, loweralkoxy, hydroxy or nitro; Y is selected from the groupconsisting of hydrogen or 1-2 radicals selected from loweralkyl, hydroxyor loweralkoxy and may be the same or different, and a pharmaceuticallyacceptable acid addition salt thereof; and (b) a pharmaceutical carriertherefor.
 30. A pharmaceutical composition of claim 29 wherein thecompound is [2-[(3-amino-2-pyridinyl)amino]phenyl]phenylmethanone.
 31. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-4-chlorophenyl]phenylmethanone.
 32. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](4-methylphenyl)methanone.
 33. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-5-chlorophenyl](2-chlorophenyl)methanone.34. A pharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-3-chlorophenyl]phenylmethanone.
 35. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]-(4-fluorophenyl)phenylmethanone.
 36. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](3-chlorophenyl)methanone.
 37. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](4-fluorophenyl)methanone.
 38. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](3-trifluoromethylphenyl)methanone.39. A pharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](3-fluorophenyl)methanone.
 40. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](2-fluorophenyl)methanone.
 41. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](2-chlorophenyl)methanone.
 42. Apharmaceutical composition of claim 29 wherein the compound is[2-[(3-amino-2-pyridinyl)amino]phenyl](2-bromophenyl)methanone.